Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005172 vascular endothelial growth factor receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA binds to both VEGFR1 (FLT1) and VEGFR2 (KDR) receptors. This is a core molecular function shared by all VEGFA isoforms including VEGF121, VEGF165, VEGF189, VEGF206, and VEGF165B. The UniProt entry explicitly states binding to FLT1/VEGFR1 and KDR/VEGFR2 receptors. Importantly, even the anti-angiogenic VEGF165B isoform binds to KDR/VEGFR2, though it does not activate downstream signaling. The deep research confirms VEGFA binds to VEGFR1 with approximately 50-fold higher affinity than VEGFR2 [VEGFA-deep-research-perplexity.md]. Reason: Core molecular function of VEGFA. All isoforms bind VEGF receptors, making this annotation universally applicable to the gene product. Well-supported by IBA phylogenetic inference and extensive experimental literature. Supporting Evidence: PMID:7929439 Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR. file:human/VEGFA/VEGFA-deep-research-perplexity.md provider: perplexity
GO:0008083 growth factor activity	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA is a canonical growth factor that stimulates endothelial cell proliferation through VEGFR2 signaling. The deep research confirms VEGFA stimulates multiple cellular responses including proliferation, survival, and migration. VEGF165 induces approximately 27% increase in HUVEC proliferation. However, this is true for pro-angiogenic isoforms (VEGF121/165/189/206) but NOT for VEGF165B which lacks mitogenic activity. Reason: Core molecular function. Growth factor activity is well-documented for the major pro-angiogenic isoforms. The IBA inference is phylogenetically sound. Supporting Evidence: PMID:21771332 VEGF stimulated HUVEC proliferation by 27% relative to untreated cells
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA is the canonical ligand that activates VEGF receptor signaling pathways through VEGFR1 and VEGFR2. Binding induces receptor dimerization and autophosphorylation, activating downstream PLCgamma-PKC-MAPK, PI3K-Akt, and p38 MAPK pathways. VEGF165B also binds receptors but initiates only weak signaling insufficient for angiogenic responses [VEGFA-deep-research-perplexity.md]. Reason: Core biological process. VEGFA is the defining ligand for VEGFR signaling pathways. All isoforms engage receptors, though with different downstream consequences. Supporting Evidence: PMID:7929439 The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA is a secreted growth factor that functions in the extracellular space. It contains an N-terminal signal sequence targeting it to the secretory pathway. However, isoform localization varies: VEGF121 is freely diffusible, VEGF165 has intermediate bioavailability, while VEGF189/206 are matrix-bound. Substantial intracrine functions have also been documented [VEGFA-deep-research-perplexity.md]. Reason: Core cellular component for the secreted protein. While some intracrine signaling exists, the primary function is as an extracellular signaling molecule.
GO:0038084 vascular endothelial growth factor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: This is essentially the same as GO:0048010 (vascular endothelial growth factor receptor signaling pathway). VEGFA is the canonical ligand initiating VEGF signaling through VEGFR1/2 receptors. Both pro-angiogenic and anti-angiogenic isoforms participate in this pathway, though with different outcomes. Reason: Core biological process. VEGFA is the defining ligand of the VEGF signaling pathway. Note this term (GO:0038084) is a child of GO:0048010. Supporting Evidence: PMID:20660291 gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
GO:0042056 chemoattractant activity	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA functions as a chemoattractant for endothelial cells, promoting their directed migration during angiogenesis. It also serves as a chemoattractant for monocytes and macrophages via VEGFR1. The deep research notes VEGF acts as a chemoattractant for endothelial cells and inflammatory cells including macrophages. Reason: Core molecular function. Chemoattractant activity is essential for VEGFA's role in angiogenesis and inflammation. Supporting Evidence: PMID:7929439 The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
GO:0050930 induction of positive chemotaxis	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA induces positive chemotaxis of endothelial cells towards the VEGF source, essential for directed vessel sprouting during angiogenesis. This is mediated primarily through VEGFR2 signaling and downstream Rac1/Cdc42 activation. Reason: Core biological process. Chemotactic guidance of endothelial cells is essential for VEGFA's angiogenic function. Supporting Evidence: PMID:7929439 The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
GO:0060754 positive regulation of mast cell chemotaxis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: VEGFA can regulate mast cell chemotaxis through VEGFR1 and VEGFR2 expressed on mast cells. This is a peripheral function related to VEGFA's broader roles in inflammation and immune modulation rather than a core angiogenic function. Reason: While VEGFA does regulate immune cell chemotaxis, mast cell chemotaxis is not a core function. This represents a pleiotropic effect in inflammatory contexts.
GO:0002040 sprouting angiogenesis	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA is the master regulator of sprouting angiogenesis. It promotes tip cell selection, endothelial cell migration, proliferation, and vessel lumen formation. CRITICAL ISOFORM NOTE: This applies to pro-angiogenic isoforms (VEGF121/165/189/206) but NOT to VEGF165B, which is anti-angiogenic and inhibits sprouting. Reason: Core function for the majority of VEGFA isoforms. While VEGF165B inhibits angiogenesis, the predominant isoforms are pro-angiogenic. The IBA annotation captures the conserved ancestral function. Isoform-specific annotation would require GO annotation extensions.
GO:0001666 response to hypoxia	IBA GO_REF:0000033	ACCEPT	Summary: VEGFA expression is strongly induced by hypoxia through HIF-1alpha stabilization. This is a key regulatory mechanism ensuring VEGFA is produced when tissues need increased vascularization. The protein itself also has structural adaptations (cystine-knot) enabling proper folding under hypoxic conditions. Reason: Core regulatory relationship. Hypoxia-induced VEGFA expression is one of the most well-characterized gene regulatory responses in mammalian biology.
GO:0001525 angiogenesis	IEA GO_REF:0000120	ACCEPT	Summary: VEGFA is the master regulator of angiogenesis. This IEA annotation correctly captures the core function. ISOFORM NOTE: Pro-angiogenic isoforms (VEGF121/165/189/206) promote angiogenesis; VEGF165B is anti-angiogenic. Reason: Core biological process. IEA is consistent with extensive experimental evidence. The term is appropriately general for the gene-level annotation.
GO:0002376 immune system process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: VEGFA has roles in immune modulation including macrophage chemotaxis and polarization. However, this term is very broad and over-general for the specific immune functions of VEGFA. Reason: While VEGFA does have immune-related functions (macrophage recruitment, M2 polarization), the term "immune system process" is too broad. More specific terms like macrophage chemotaxis would be more informative.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: VEGFA is a secreted growth factor that functions primarily in the extracellular region. Contains an N-terminal signal peptide for secretory pathway targeting. Reason: Core cellular component. VEGFA is secreted and functions extracellularly. This is broader than GO:0005615 (extracellular space) but still accurate.
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Nuclear-localized VEGF has been detected in multiple cell types as part of intracrine signaling. The deep research notes nuclear VEGF and VEGFR2 participate in direct regulation of gene expression and metabolic homeostasis. Reason: While nuclear VEGFA exists and has functional significance for intracrine signaling, the primary localization and function is extracellular. Nuclear localization represents a secondary function.
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: VEGFA transits through the cytoplasm during synthesis and secretion. Intracrine VEGF signaling also involves cytoplasmic pools of VEGF and its receptors. Reason: Cytoplasmic localization is a transit compartment during biosynthesis. The functional localization is extracellular. This is accurate but not a core functional location.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: VEGFA undergoes dimerization and disulfide bond formation in the ER during biosynthesis. The deep research notes that VEGFA can efficiently complete disulfide bond formation in the ER even under hypoxia. Reason: ER is a transit compartment during biosynthesis, not a functional location. Accurate but represents biosynthetic pathway rather than functional localization.
GO:0005794 Golgi apparatus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: VEGFA transits through the Golgi for N-linked glycosylation during secretion. Post-Golgi transport depends on glycosylation modifications. Reason: Golgi is a transit compartment for secretion, not a functional location. Accurate but represents biosynthetic pathway.
GO:0008083 growth factor activity	IEA GO_REF:0000120	ACCEPT	Summary: VEGFA is a canonical growth factor stimulating endothelial cell proliferation and survival. This IEA annotation is consistent with the IBA annotation and extensive experimental evidence. Reason: Core molecular function. Duplicates IBA annotation but IEA provides independent computational evidence support.
GO:0008201 heparin binding	IEA GO_REF:0000120	ACCEPT	Summary: Heparin binding is ISOFORM-SPECIFIC. VEGF121 lacks heparin binding (no exons 6/7). VEGF165 has intermediate heparin affinity (exon 7 only). VEGF189/206 have high heparin affinity (exons 6 and 7). This is a key determinant of bioavailability. Reason: Important molecular function, though isoform-specific. The predominant isoforms (VEGF165, VEGF189) do bind heparin. Annotation is valid at gene level.
GO:0008284 positive regulation of cell population proliferation	IEA GO_REF:0000117	ACCEPT	Summary: VEGFA stimulates endothelial cell proliferation through VEGFR2-PLCgamma-PKC-MAPK signaling. Also promotes proliferation of other cell types. ISOFORM NOTE: VEGF165B does not stimulate proliferation. Reason: Core biological process for pro-angiogenic isoforms. Proliferation is essential for angiogenesis. The term is appropriately general.
GO:0016020 membrane	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: VEGFA associates with the plasma membrane surface before shedding. The deep research notes substantial fraction localizes to outer plasma membrane in punctate pattern. Reason: Membrane association is transient during secretion. Primary function is extracellular. This InterPro-based annotation is less informative than specific localization terms.
GO:0030154 cell differentiation	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: VEGFA promotes endothelial cell differentiation during vascular development and angiogenesis. However, this term is very broad. Reason: While VEGFA affects endothelial cell differentiation, the term is too general. More specific terms like vasculogenesis or endothelial cell differentiation would be more informative.
GO:0042056 chemoattractant activity	IEA GO_REF:0000117	ACCEPT	Summary: VEGFA is a chemoattractant for endothelial cells and monocytes/macrophages. This IEA annotation is consistent with the IBA annotation. Reason: Core molecular function. Duplicates IBA but IEA provides independent evidence support.
GO:0043117 positive regulation of vascular permeability	IEA GO_REF:0000117	ACCEPT	Summary: VEGFA (originally called Vascular Permeability Factor/VPF) is a potent inducer of vascular permeability through phosphorylation of junctional proteins and Rac1-mediated cytoskeletal changes. ISOFORM NOTE: Pro-angiogenic isoforms only. Reason: Core biological process. VEGFA was originally identified as a permeability factor. This is a defining function of the protein.
GO:0043184 vascular endothelial growth factor receptor 2 binding	IEA GO_REF:0000117	ACCEPT	Summary: VEGFA binds VEGFR2/KDR, the main transducer of angiogenic signals. All isoforms including VEGF165B bind VEGFR2, though with different signaling outcomes. Reason: Core molecular function. VEGFR2 binding is essential for VEGFA signaling. Supporting Evidence: PMID:7929439 Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR.
GO:0045766 positive regulation of angiogenesis	IEA GO_REF:0000117	ACCEPT	Summary: VEGFA is the master positive regulator of angiogenesis. CRITICAL ISOFORM NOTE: This applies to pro-angiogenic isoforms (VEGF121/165/189/206) but NOT to VEGF165B, which INHIBITS angiogenesis and should have a negative regulation annotation. Reason: Core function for pro-angiogenic isoforms. The annotation correctly captures the predominant function. A separate annotation for VEGF165B anti-angiogenic activity would be needed for completeness.
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: VEGFA is the canonical ligand for VEGFR signaling. This IEA annotation is consistent with the IBA annotations for this pathway. Reason: Core biological process. Duplicates IBA but provides independent evidence support.
GO:0051781 positive regulation of cell division	IEA GO_REF:0000043	ACCEPT	Summary: VEGFA promotes endothelial cell division through MAPK signaling. This is related to its proliferative effects. Reason: Valid biological process annotation. Cell division is required for angiogenesis.
GO:0005515 protein binding	IPI PMID:10543948 Solution structure of the VEGF-binding domain of Flt-1: comp...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation. VEGFA binds multiple proteins including receptors (VEGFR1, VEGFR2, NRP1), matrix components, and coreceptors. Reason: Protein binding is too generic. More specific binding terms (VEGFR binding, heparin binding) are more informative. This is a common over-annotation pattern. Supporting Evidence: PMID:10543948 Solution structure of the VEGF-binding domain of Flt-1: comparison of its free and bound states.
GO:0005515 protein binding	IPI PMID:16763549 Glycosaminoglycan modification of neuropilin-1 modulates VEG...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation based on neuropilin-1 and VEGFR2 interaction studies. Reason: Protein binding is too generic. The specific interaction partners (NRP1, VEGFR2) warrant more specific GO terms. Supporting Evidence: PMID:16763549 Jun 8. Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.
GO:0005515 protein binding	IPI PMID:17222790 Blocking neuropilin-1 function has an additive effect with a...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation based on neuropilin-1 interaction studies. Reason: Protein binding is too generic. Neuropilin binding would be more informative. Supporting Evidence: PMID:17222790 Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth.
GO:0005515 protein binding	IPI PMID:20660291 Gremlin is a novel agonist of the major proangiogenic recept...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from Gremlin-VEGFR2 study context. Reason: Protein binding is too generic. Supporting Evidence: PMID:20660291 gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
GO:0005515 protein binding	IPI PMID:21653826 VEGF binding to NRP1 is essential for VEGF stimulation of en...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation based on NRP1 interaction study. Reason: Protein binding is too generic. NRP1 binding would be more informative. Supporting Evidence: PMID:21653826 2011 Jun 8. VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation.
GO:0005515 protein binding	IPI PMID:23374253 Endorepellin laminin-like globular 1/2 domains bind Ig3-5 of...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation based on endorepellin-VEGFR2 study. Reason: Protein binding is too generic. Supporting Evidence: PMID:23374253 Endorepellin laminin-like globular 1/2 domains bind Ig3-5 of vascular endothelial growth factor (VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells.
GO:0005515 protein binding	IPI PMID:23583373 Early VEGFR2 activation in response to flow is VEGF-dependen...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation based on VEGFR2 interaction study. Reason: Protein binding is too generic. VEGFR2 binding is already annotated specifically. Supporting Evidence: PMID:23583373 Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from proteome-scale interactome study. Reason: Protein binding is too generic for high-throughput interactome data. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:9393862 Crystal structure at 1.7 A resolution of VEGF in complex wit...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from VEGF-Flt1 crystal structure study. Reason: Protein binding is too generic. VEGFR1 binding would be more informative. Supporting Evidence: PMID:9393862 Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.
GO:0042802 identical protein binding	IPI PMID:12207021 The cystine knot promotes folding and not thermodynamic stab...	ACCEPT	Summary: VEGFA forms homodimers stabilized by interchain disulfide bonds between Cys51 and Cys60. Dimerization is essential for receptor activation. Reason: Core molecular function. VEGFA homodimerization is required for biological activity. This is more specific and informative than generic protein binding. Supporting Evidence: PMID:12207021 2002 Aug 30. The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor.
GO:0042802 identical protein binding	IPI PMID:25132001 Development of a highly-potent anti-angiogenic VEGF8-109 het...	ACCEPT	Summary: VEGFA homodimerization study. Consistent with the essential role of dimerization in VEGFA function. Reason: Core molecular function. Homodimerization is essential for VEGFA activity. Supporting Evidence: PMID:25132001 Development of a highly-potent anti-angiogenic VEGF8-109 heterodimer by directed blocking of its VEGFR-2 binding site.
GO:0005615 extracellular space	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of IBA annotation. VEGFA functions in the extracellular space. Reason: Core cellular component. Consistent with IBA annotation.
GO:0010719 negative regulation of epithelial to mesenchymal transition	IEA GO_REF:0000107	UNDECIDED	Summary: IEA transferred from Ensembl ortholog. The role of VEGFA in EMT is complex and context-dependent. In some contexts VEGFA may inhibit EMT but this is not a well-established core function. Reason: EMT regulation by VEGFA is complex. This ortholog-transferred annotation may not reflect human VEGFA function. Requires literature review.
GO:0031290 retinal ganglion cell axon guidance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: VEGFA has documented roles in neural guidance including retinal development. This is a pleiotropic developmental function beyond core angiogenesis. Reason: VEGFA has neural guidance functions but this is peripheral to its core angiogenic role. Valid developmental function.
GO:0035924 cellular response to vascular endothelial growth factor stimulus	IEA GO_REF:0000107	REMOVE	Summary: Circular annotation - VEGFA is the stimulus, not the responder. This annotation would be appropriate for VEGF receptors, not VEGFA itself. Reason: Inappropriate annotation. VEGFA is the ligand that causes the stimulus, not a gene product that responds to VEGF stimulus.
GO:0048842 positive regulation of axon extension involved in axon guidance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: VEGFA has neural guidance functions including axon extension regulation. This is a pleiotropic developmental function. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0050918 positive chemotaxis	IEA GO_REF:0000107	ACCEPT	Summary: VEGFA induces positive chemotaxis of endothelial cells and other cell types. Consistent with IBA chemoattractant activity annotation. Reason: Core biological process. Chemotaxis is essential for angiogenesis.
GO:0071679 commissural neuron axon guidance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: VEGFA has documented roles in neural guidance. This is a pleiotropic developmental function. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0090190 positive regulation of branching involved in ureteric bud morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: VEGFA has roles in kidney development including ureteric bud morphogenesis. This is a pleiotropic developmental function. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0097475 motor neuron migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: VEGFA has neural guidance functions. Motor neuron migration may be affected by VEGFA signaling as part of developmental neurovascular coordination. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0120162 positive regulation of cold-induced thermogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: VEGFA has documented roles in brown adipose tissue function and thermogenesis. The deep research notes autocrine VEGFA is essential for mitochondrial function in brown adipocytes. Reason: Valid metabolic function but peripheral to core angiogenic role.
GO:0005576 extracellular region	TAS Reactome:R-HSA-1235037	ACCEPT	Summary: Reactome pathway annotation for VEGFA expression. VEGFA is secreted to the extracellular region. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-194310	ACCEPT	Summary: Reactome pathway annotation for VEGF-A,C,D binding to VEGFR2. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-194311	ACCEPT	Summary: Reactome pathway annotation for VEGFA,B,PLGF binding to VEGFR1. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-195378	ACCEPT	Summary: Reactome pathway annotation for homodimerization of VEGF proteins. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420083	ACCEPT	Summary: Reactome pathway annotation for PTK2 recruitment to VEGFR2 signaling complex. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420099	ACCEPT	Summary: Reactome pathway annotation for VEGFR2-SHB binding. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420107	ACCEPT	Summary: Reactome pathway annotation for VEGFR2-SHC2 binding. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420117	ACCEPT	Summary: Reactome pathway annotation for VEGFR2 autophosphorylation. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420121	ACCEPT	Summary: Reactome pathway annotation for SFK phosphorylation of PLCgamma1. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420128	ACCEPT	Summary: Reactome pathway annotation for SRC-1 phosphorylation of SHB. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420140	ACCEPT	Summary: Reactome pathway annotation for SRC-1 recruitment to VEGFR2. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420143	ACCEPT	Summary: Reactome pathway annotation for VEGFR2-SH2D2A binding. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420153	ACCEPT	Summary: Reactome pathway annotation for VEGFR2-PLCgamma1 binding. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420202	ACCEPT	Summary: Reactome pathway annotation for PLCgamma1 translocation to plasma membrane. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-4420206	ACCEPT	Summary: Reactome pathway annotation. VEGFA is secreted extracellularly. Reason: Core cellular component. Consistent with other annotations.
GO:0005576 extracellular region	TAS Reactome:R-HSA-481007	ACCEPT	Summary: Reactome pathway annotation for platelet degranulation. Reason: Core cellular component. VEGFA is released during platelet degranulation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218640	ACCEPT	Summary: Reactome pathway annotation for NRP1-VEGF binding. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218642	ACCEPT	Summary: Reactome pathway annotation for NRP1-VEGFR signaling complex. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218643	ACCEPT	Summary: Reactome pathway annotation for VEGF signaling. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218645	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218804	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218806	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218809	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218811	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218812	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218814	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218815	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218818	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218819	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218820	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218822	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218824	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218826	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218830	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218832	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218836	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218838	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218839	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218847	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218851	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5218854	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5357429	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5357432	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5357479	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6789615	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-8864936	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-9679477	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0005576 extracellular region	TAS Reactome:R-HSA-9691215	ACCEPT	Summary: Reactome pathway annotation. Reason: Core cellular component.
GO:0031093 platelet alpha granule lumen	TAS Reactome:R-HSA-481007	ACCEPT	Summary: VEGFA is stored in platelet alpha granules and released during platelet degranulation. This contributes to wound healing and vascular repair. Reason: Valid cellular component. Platelet storage is a documented function.
GO:0038084 vascular endothelial growth factor signaling pathway	IDA PMID:20660291 Gremlin is a novel agonist of the major proangiogenic recept...	ACCEPT	Summary: Experimental study demonstrating VEGFA activates VEGFR2 signaling. The paper identifies gremlin as a novel VEGFR2 agonist distinct from VEGF family ligands, validating VEGFA as the canonical VEGFR2 ligand. Reason: Core biological process. IDA evidence from direct experimental demonstration. Supporting Evidence: PMID:20660291 gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
GO:0001525 angiogenesis	IDA PMID:21771332 Glioblastoma-derived leptin induces tube formation and growt...	ACCEPT	Summary: Study comparing VEGF and leptin effects on endothelial cells. VEGF (50 ng/mL) stimulated HUVEC proliferation by 27% and tube formation by ~60%. This directly demonstrates VEGFA angiogenic activity. Reason: Core biological process with direct experimental evidence. Supporting Evidence: PMID:21771332 VEGF stimulated HUVEC proliferation by 27% relative to untreated cells
GO:0001569 branching involved in blood vessel morphogenesis	IMP PMID:23688497 MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogen...	UNDECIDED	Summary: IMP evidence for VEGFA role in blood vessel branching morphogenesis. Publication not in cache - based on annotation appears to demonstrate VEGFA involvement in vessel branching. Reason: Publication PMID:23688497 not available for verification. Blood vessel branching is consistent with known VEGFA functions. Supporting Evidence: PMID:23688497 Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogen...	ACCEPT	Summary: IDA evidence for VEGFA stimulating endothelial cell proliferation. Function is well-established from multiple other sources. Reason: Core function. Function is well-established from multiple IDA and IBA sources; additional IDA evidence is consistent. Supporting Evidence: PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.
GO:0038033 positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway	IDA PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogen...	UNDECIDED	Summary: Very specific GO term capturing VEGFA-induced endothelial chemotaxis via VEGFR signaling. This is consistent with established VEGFA function. Reason: Publication PMID:31915155 not available for verification. Function is consistent with known biology but specific evidence cannot be confirmed. Supporting Evidence: PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.
GO:0043066 negative regulation of apoptotic process	IMP PMID:11461089 Vascular endothelial growth factor (VEGF) upregulates BCL-2 ...	ACCEPT	Summary: IMP evidence for VEGFA anti-apoptotic function. VEGFA promotes endothelial cell survival through PI3K-Akt signaling pathway. Reason: Core function. Anti-apoptotic function is well-established from deep research documenting Akt-mediated survival signaling. Consistent with other IMP evidence. Supporting Evidence: PMID:11461089 Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells.
GO:1900748 positive regulation of vascular endothelial growth factor signaling pathway	IDA PMID:23688497 MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogen...	UNDECIDED	Summary: Autocrine/positive feedback annotation for VEGFA on its own signaling pathway. VEGFA can amplify its own signaling through various mechanisms. Reason: Publication PMID:23688497 not available for verification. Supporting Evidence: PMID:23688497 Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
GO:1905555 positive regulation of blood vessel branching	IDA PMID:20123964 Lipid phosphate phosphatase 3 stabilization of beta-catenin ...	UNDECIDED	Summary: IDA evidence for VEGFA promoting vessel branching. Publication not in cache. Vessel branching is a core VEGFA angiogenic function. Reason: Publication PMID:20123964 not available for verification. Supporting Evidence: PMID:20123964 Feb 1. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
GO:0038084 vascular endothelial growth factor signaling pathway	IMP PMID:19148554 Angiopoietin-1 reduces vascular endothelial growth factor-in...	ACCEPT	Summary: IMP evidence for VEGFA in VEGF signaling pathway. Core function established from multiple sources. Reason: Core biological process. VEGFA is the canonical ligand for VEGF signaling; function is well-established from IBA and other IDA sources. Supporting Evidence: PMID:19148554 Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.
GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway	IDA PMID:18059339 The zinc-finger transcription factor, early growth response ...	ACCEPT	Summary: VEGFA activates PLCgamma through VEGFR2 signaling. The study shows VEGF signals through PKC pathway to activate transcription factor Egr3. Reason: Core signaling mechanism. VEGFR2-PLCgamma-PKC is a major VEGFA signaling pathway. Supporting Evidence: PMID:18059339 VEGF induced a rapid increase in Egr-dependent transcriptional activation mediated via its major signalling receptor, VEGFR2/KDR, and the protein kinase C (PKC) pathway
GO:0042056 chemoattractant activity	IDA PMID:18059339 The zinc-finger transcription factor, early growth response ...	ACCEPT	Summary: VEGFA promotes endothelial cell migration. The study demonstrates VEGF mediates endothelial cell migration and tubulogenesis through Egr3. Reason: Core molecular function. Direct experimental evidence for chemoattractant activity. Supporting Evidence: PMID:18059339 Inhibition of Egr3 gene expression by RNA interference was effective in inhibiting basal and VEGF-induced Egr3 gene expression, and it also inhibited VEGF-mediated endothelial cell proliferation, migration and tubulogenesis
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IDA PMID:18059339 The zinc-finger transcription factor, early growth response ...	ACCEPT	Summary: Direct evidence that VEGF signals through VEGFR2/KDR to activate PKC pathway. Reason: Core biological process with direct experimental evidence. Supporting Evidence: PMID:18059339 VEGF induced a rapid increase in Egr-dependent transcriptional activation mediated via its major signalling receptor, VEGFR2/KDR, and the protein kinase C (PKC) pathway
GO:0035767 endothelial cell chemotaxis	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	ACCEPT	Summary: Study shows VEGF induces endothelial cell migration through PKD-HSP27 pathway. Knockdown of HSP27 and PKDs markedly inhibited VEGF-induced HUVEC migration. Reason: Core biological process with direct experimental evidence for chemotaxis mechanism. Supporting Evidence: PMID:18440775 Knockdown of HSP27 and PKDs markedly inhibited VEGF-induced HUVEC migration and tubulogenesis
GO:0035767 endothelial cell chemotaxis	IDA PMID:21245381 Neuropilin-1 signaling through p130Cas tyrosine phosphorylat...	ACCEPT	Summary: IDA evidence for VEGFA-induced endothelial cell chemotaxis. Consistent with other experimental evidence. Reason: Core function. Endothelial cell chemotaxis is well-established from multiple IDA sources including PMID:18440775. Supporting Evidence: PMID:21245381 Jan 18. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.
GO:0043410 positive regulation of MAPK cascade	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	ACCEPT	Summary: VEGF activates MAPK cascade through VEGFR2 signaling. The study demonstrates VEGF-induced PKD activation leads to downstream signaling including ERK/MAPK. Reason: Core signaling pathway. VEGFR2-PLCgamma-PKC-ERK is a major VEGFA signaling cascade. Supporting Evidence: PMID:18440775 VEGF activated Protein Kinase D (PKD) via PKC
GO:0043536 positive regulation of blood vessel endothelial cell migration	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	ACCEPT	Summary: VEGF promotes endothelial cell migration. Study shows PKD-HSP27 pathway mediates VEGF-induced migration and tubulogenesis. Reason: Core biological process. Essential for angiogenesis. Supporting Evidence: PMID:18440775 Knockdown of HSP27 and PKDs markedly inhibited VEGF-induced HUVEC migration and tubulogenesis
GO:0045766 positive regulation of angiogenesis	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	ACCEPT	Summary: VEGF promotes angiogenesis. Study shows VEGF-induced tubulogenesis via PKD-HSP27 pathway. CRITICAL ISOFORM NOTE: Applies to pro-angiogenic isoforms only; VEGF165B is anti-angiogenic. Reason: Core biological process for pro-angiogenic isoforms. Supporting Evidence: PMID:18440775 PKDs and HSP27 play major roles in the angiogenic response to VEGF
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	ACCEPT	Summary: VEGF signals through VEGFR2/KDR. Study demonstrates VEGF-induced signaling through PKD pathway. Reason: Core biological process. Supporting Evidence: PMID:18440775 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IDA PMID:21245381 Neuropilin-1 signaling through p130Cas tyrosine phosphorylat...	ACCEPT	Summary: IDA evidence for VEGFR signaling. Core function supported by multiple independent references. Reason: Core function. VEGFR signaling is well-established from multiple sources; additional IDA evidence consistent. Supporting Evidence: PMID:21245381 Jan 18. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.
GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis	IDA PMID:18059339 The zinc-finger transcription factor, early growth response ...	ACCEPT	Summary: VEGF promotes cell migration in sprouting angiogenesis through Egr3-mediated transcriptional regulation. Reason: Core biological process. Supporting Evidence: PMID:18059339 it also inhibited VEGF-mediated endothelial cell proliferation, migration and tubulogenesis
GO:0031290 retinal ganglion cell axon guidance	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for neural guidance function. VEGFA has documented roles in neurovascular coordination. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0038190 VEGF-activated neuropilin signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: VEGFA binds neuropilin-1 (VEGF165 isoform specifically through exon 7). NRP1 serves as a co-receptor enhancing VEGFR2 signaling. Reason: Important signaling pathway, especially for VEGF165 isoform.
GO:0042056 chemoattractant activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation consistent with IBA and IDA evidence. Reason: Core molecular function. Multiple evidence sources support this.
GO:0048842 positive regulation of axon extension involved in axon guidance	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for neural guidance function. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0050918 positive chemotaxis	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation consistent with IEA evidence. Reason: Core biological process.
GO:0071679 commissural neuron axon guidance	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for neural guidance function. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:19652095 Response gene to complement 32, a novel hypoxia-regulated an...	UNDECIDED	Summary: IMP evidence for VEGFA regulation of transcription. Publication not in cache. VEGFA signaling is known to activate various transcription factors. Reason: Publication PMID:19652095 not available for verification. Supporting Evidence: PMID:19652095 Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor.
GO:0071456 cellular response to hypoxia	IMP PMID:19652095 Response gene to complement 32, a novel hypoxia-regulated an...	UNDECIDED	Summary: IMP evidence for VEGFA in hypoxia response. VEGFA expression is induced by hypoxia, and it also participates in cellular responses to low oxygen. Reason: Publication PMID:19652095 not available for verification. Supporting Evidence: PMID:19652095 Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor.
GO:0038084 vascular endothelial growth factor signaling pathway	NAS PMID:23878390 MicroRNA 329 suppresses angiogenesis by targeting CD146.	ACCEPT	Summary: NAS (non-traceable author statement) evidence. Consistent with core function. Reason: Core biological process. VEGFA is the canonical ligand. Supporting Evidence: PMID:23878390 Jul 22. MicroRNA 329 suppresses angiogenesis by targeting CD146.
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	NAS PMID:23878390 MicroRNA 329 suppresses angiogenesis by targeting CD146.	KEEP AS NON CORE	Summary: NAS evidence for VEGFA activation of NF-kappaB signaling. VEGFA can activate NF-kappaB through various pathways in endothelial and cancer cells. Reason: Valid signaling pathway but not core to angiogenic function. Supporting Evidence: PMID:23878390 Jul 22. MicroRNA 329 suppresses angiogenesis by targeting CD146.
GO:1902894 negative regulation of miRNA transcription	NAS PMID:23878390 MicroRNA 329 suppresses angiogenesis by targeting CD146.	KEEP AS NON CORE	Summary: NAS evidence for VEGFA regulation of miRNA transcription. VEGFA signaling can modulate miRNA expression as part of broader transcriptional effects. Reason: Secondary regulatory effect rather than core function. Supporting Evidence: PMID:23878390 Jul 22. MicroRNA 329 suppresses angiogenesis by targeting CD146.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: IDA evidence for VEGFA stimulating EC proliferation. Core function well-established. Reason: Core function. Function is well-established from multiple IDA and IBA sources. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0030297 transmembrane receptor protein tyrosine kinase activator activity	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: VEGFA activates VEGFR1 and VEGFR2, which are receptor tyrosine kinases. This is the core molecular function of VEGFA as a ligand. Reason: Core molecular function. VEGFA activates VEGFR tyrosine kinase activity. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0035924 cellular response to vascular endothelial growth factor stimulus	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	REMOVE	Summary: Circular annotation - VEGFA is the stimulus, not the responder. This annotation would be appropriate for VEGF receptors or downstream effectors, not VEGFA itself. Reason: Inappropriate annotation. VEGFA is the ligand that causes the stimulus, not a gene product that responds to VEGF stimulus. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0043536 positive regulation of blood vessel endothelial cell migration	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: IDA evidence for VEGFA promoting EC migration. Core function well-established. Reason: Core function. EC migration is well-established from multiple IDA sources. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	UNDECIDED	Summary: IDA evidence for VEGFA regulating transcription. Publication not in cache. Reason: Publication PMID:20497126 not available. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IMP PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: IMP evidence for VEGFR signaling. Core function supported by multiple independent references. Reason: Core function. VEGFR signaling is well-established from multiple sources; additional IMP evidence consistent. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:2001028 positive regulation of endothelial cell chemotaxis	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	UNDECIDED	Summary: VEGFA induces endothelial cell chemotaxis. This is consistent with chemoattractant activity and sprouting angiogenesis function. Reason: Publication PMID:20497126 not available. Function consistent with other evidence. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0038084 vascular endothelial growth factor signaling pathway	IMP PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulatin...	ACCEPT	Summary: IMP evidence for VEGF signaling. Core function established from multiple sources. Reason: Core biological process. VEGFA is the canonical ligand for VEGF signaling. Supporting Evidence: PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
GO:0048018 receptor ligand activity	IMP PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulatin...	ACCEPT	Summary: VEGFA is a receptor ligand for VEGFR1, VEGFR2, and neuropilins. This is a core molecular function. Reason: Core molecular function. VEGFA is the canonical VEGFR ligand. Supporting Evidence: PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
GO:0036324 vascular endothelial growth factor receptor-2 signaling pathway	IMP PMID:23688497 MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogen...	ACCEPT	Summary: VEGFA activates VEGFR2 signaling. This is the primary signaling receptor for angiogenic effects. Reason: Core biological process. VEGFR2 is the main angiogenic signaling receptor. Supporting Evidence: PMID:23688497 Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
GO:0005515 protein binding	IPI PMID:17446437 Association of ATP1A1 and dear single-nucleotide polymorphis...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation. Reason: Protein binding is too generic. More specific binding terms are more informative. Supporting Evidence: PMID:17446437 Epub 2007 Apr 19. Association of ATP1A1 and dear single-nucleotide polymorphism haplotypes with essential hypertension: sex-specific and haplotype-specific effects.
GO:0010629 negative regulation of gene expression	IDA PMID:28977001 MicroRNA-30b controls endothelial cell capillary morphogenes...	UNDECIDED	Summary: IDA evidence for VEGFA negative regulation of gene expression. Publication not in cache. Reason: Publication PMID:28977001 not available. Supporting Evidence: PMID:28977001 eCollection 2017. MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2.
GO:0005515 protein binding	IPI PMID:25825981 EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from EMMPRIN study. Reason: Protein binding is too generic. Supporting Evidence: PMID:25825981 EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.
GO:0043184 vascular endothelial growth factor receptor 2 binding	IPI PMID:25825981 EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its...	ACCEPT	Summary: VEGFA binds VEGFR2. Core molecular function shared by all VEGFA isoforms. Reason: Core molecular function. Supporting Evidence: PMID:25825981 EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IDA PMID:1312256 The fms-like tyrosine kinase, a receptor for vascular endoth...	ACCEPT	Summary: Early IDA evidence for VEGFR signaling. This paper identified Flt-1 as a VEGF receptor. Reason: Core function. Historic paper identifying VEGFR1/Flt-1 as VEGF receptor; VEGFR signaling is well-established. Supporting Evidence: PMID:1312256 The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
GO:0048010 vascular endothelial growth factor receptor signaling pathway	IDA PMID:7929439 Different signal transduction properties of KDR and Flt1, tw...	ACCEPT	Summary: Classic paper demonstrating VEGF signals through KDR (VEGFR2). Shows VEGF induces chemotaxis and mitogenicity in KDR-expressing cells. Reason: Core biological process with landmark experimental evidence. Supporting Evidence: PMID:7929439 The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
GO:0043536 positive regulation of blood vessel endothelial cell migration	IMP PMID:23688497 MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogen...	ACCEPT	Summary: IMP evidence for EC migration. Core function well-established. Reason: Core function. EC migration is well-established from multiple IDA sources. Supporting Evidence: PMID:23688497 Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
GO:0061042 vascular wound healing	IMP PMID:23688497 MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogen...	ACCEPT	Summary: VEGFA promotes wound healing through stimulation of angiogenesis. This is a physiological context for VEGFA angiogenic function. Reason: Valid biological process. Wound healing is a key physiological context for angiogenesis. Supporting Evidence: PMID:23688497 Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
GO:1903589 positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	IMP PMID:30106099 Overexpression of miR‑21 is involved in acute monocytic leuk...	UNDECIDED	Summary: IMP evidence for sprouting angiogenesis. Publication not in cache. Reason: Publication PMID:30106099 not available. Supporting Evidence: PMID:30106099 Aug 6. Overexpression of miR‑21 is involved in acute monocytic leukemia‑associated angiogenesis by targeting IL‑12.
GO:0001569 branching involved in blood vessel morphogenesis	IMP PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulatin...	UNDECIDED	Summary: IMP evidence for vessel branching. Publication not in cache. Reason: Publication PMID:23083510 not available. Supporting Evidence: PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis	IMP PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulatin...	UNDECIDED	Summary: IMP evidence for migration in sprouting angiogenesis. Publication not in cache. Reason: Publication PMID:23083510 not available. Supporting Evidence: PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
GO:1901165 positive regulation of trophoblast cell migration	IMP PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulatin...	KEEP AS NON CORE	Summary: VEGFA promotes trophoblast migration during placental development. This is a developmental function beyond core angiogenesis. Reason: Valid developmental function but peripheral to core angiogenic role. Supporting Evidence: PMID:23083510 miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
GO:0010629 negative regulation of gene expression	IMP PMID:19148554 Angiopoietin-1 reduces vascular endothelial growth factor-in...	UNDECIDED	Summary: IMP evidence for gene expression regulation. Publication not in cache. Reason: Publication PMID:19148554 not available. Supporting Evidence: PMID:19148554 Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.
GO:1905604 negative regulation of blood-brain barrier permeability	IMP PMID:19148554 Angiopoietin-1 reduces vascular endothelial growth factor-in...	UNDECIDED	Summary: VEGFA effects on BBB are complex. It can both increase and decrease permeability depending on context and isoform. Reason: Publication PMID:19148554 not available. BBB effects are context-dependent. Supporting Evidence: PMID:19148554 Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.
GO:0005912 adherens junction	IDA PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeab...	UNDECIDED	Summary: VEGFA affects adherens junction organization as part of permeability regulation. Publication not in cache. Reason: Publication PMID:26598555 not available. Supporting Evidence: PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
GO:0043117 positive regulation of vascular permeability	IDA PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeab...	ACCEPT	Summary: VEGFA (originally VPF) is a potent inducer of vascular permeability. This is a core function. ISOFORM NOTE: Pro-angiogenic isoforms only. Reason: Core biological process. VEGFA was originally identified as VPF. Supporting Evidence: PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
GO:1903392 negative regulation of adherens junction organization	IDA PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeab...	ACCEPT	Summary: VEGFA disrupts adherens junctions to increase permeability. Mechanism involves VE-cadherin phosphorylation and internalization. Reason: Part of permeability regulation mechanism. Supporting Evidence: PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
GO:2000048 negative regulation of cell-cell adhesion mediated by cadherin	IDA PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeab...	ACCEPT	Summary: VEGFA promotes VE-cadherin internalization reducing cell-cell adhesion. Part of permeability regulation. Reason: Part of permeability regulation mechanism. Supporting Evidence: PMID:26598555 VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
GO:1903141 negative regulation of establishment of endothelial barrier	IDA PMID:20048167 Src-induced tyrosine phosphorylation of VE-cadherin is not s...	ACCEPT	Summary: VEGFA disrupts endothelial barrier function to increase permeability. Related to VPF activity. Reason: Core function related to vascular permeability factor activity. Supporting Evidence: PMID:20048167 2010 Jan 4. Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers.
GO:0120162 positive regulation of cold-induced thermogenesis	ISS PMID:26683794 Autocrine effect of vascular endothelial growth factor-A is ...	KEEP AS NON CORE	Summary: VEGFA has roles in brown adipose tissue thermogenesis. ISS evidence from mouse studies. Reason: Valid metabolic function but peripheral to core angiogenic role. Supporting Evidence: PMID:26683794 2015 Sep 25. Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes.
GO:0010749 regulation of nitric oxide mediated signal transduction	IDA PMID:16150726 Thrombospondin-1 inhibits endothelial cell responses to nitr...	ACCEPT	Summary: VEGFA activates eNOS to produce NO, a key mediator of vascular relaxation and permeability. Reason: Important signaling mechanism for VEGFA vascular effects. Supporting Evidence: PMID:16150726 Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner.
GO:0097533 cellular stress response to acid chemical	IDA PMID:26299712 High concentrations of uric acid inhibit angiogenesis via re...	UNDECIDED	Summary: IDA evidence for acid stress response. Publication not in cache. Reason: Publication PMID:26299712 not available. Supporting Evidence: PMID:26299712 High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.
GO:1903672 positive regulation of sprouting angiogenesis	IDA PMID:26299712 High concentrations of uric acid inhibit angiogenesis via re...	ACCEPT	Summary: VEGFA is the master regulator of sprouting angiogenesis. Publication not in cache. Reason: Core biological process. Consistent with extensive evidence. Supporting Evidence: PMID:26299712 High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.
GO:1903672 positive regulation of sprouting angiogenesis	IGI PMID:25251394 MicroRNA-377 regulates mesenchymal stem cell-induced angioge...	UNDECIDED	Summary: IGI evidence for sprouting angiogenesis. Publication not in cache. Reason: Publication PMID:25251394 not available. Supporting Evidence: PMID:25251394 eCollection 2014. MicroRNA-377 regulates mesenchymal stem cell-induced angiogenesis in ischemic hearts by targeting VEGF.
GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis	IGI PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he...	UNDECIDED	Summary: IGI evidence for migration in sprouting angiogenesis. Publication not in cache. Reason: Publication PMID:24844779 not available. Supporting Evidence: PMID:24844779 Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
GO:1903589 positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	IGI PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he...	UNDECIDED	Summary: IGI evidence for EC proliferation in sprouting. Publication not in cache. Reason: Publication PMID:24844779 not available. Supporting Evidence: PMID:24844779 Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis	IMP PMID:24865854 Dysregulated miR-361-5p/VEGF axis in the plasma and endothel...	UNDECIDED	Summary: IMP evidence for migration in sprouting. Publication not in cache. Reason: Publication PMID:24865854 not available. Supporting Evidence: PMID:24865854 eCollection 2014. Dysregulated miR-361-5p/VEGF axis in the plasma and endothelial progenitor cells of patients with coronary artery disease.
GO:0097475 motor neuron migration	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for neural guidance function. Reason: Valid developmental function but peripheral to core angiogenic role.
GO:0008284 positive regulation of cell population proliferation	IMP PMID:26268439 p75(NTR)-dependent activation of NF-κB regulates microRNA-50...	ACCEPT	Summary: VEGFA stimulates cell proliferation through VEGFR2-PLCgamma-PKC-MAPK signaling. Core function for pro-angiogenic isoforms. Reason: Core biological process. Deep research confirms VEGFA promotes endothelial cell proliferation. Pro-angiogenic isoforms only; VEGF165b lacks mitogenic activity. Supporting Evidence: PMID:26268439 p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.
GO:0001934 positive regulation of protein phosphorylation	IDA PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated...	ACCEPT	Summary: VEGFA binding to VEGFR2 induces receptor autophosphorylation and downstream phosphorylation cascades. Reason: Core function. VEGFR2 autophosphorylation at Y1175, Y951, Y1214 initiates downstream signaling cascades (deep research). Supporting Evidence: PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
GO:0010595 positive regulation of endothelial cell migration	IDA PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated...	ACCEPT	Summary: VEGFA promotes endothelial cell migration through Y1214-NCK-p38 MAPK pathway and actin remodeling. Reason: Core function for angiogenesis. Deep research confirms VEGF induces chemotaxis and directed migration via Rac1/Cdc42 activation. Supporting Evidence: PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
GO:0031334 positive regulation of protein-containing complex assembly	IDA PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated...	KEEP AS NON CORE	Summary: VEGFA signaling may promote assembly of focal adhesion complexes during cell migration. Reason: Supporting function. VEGF promotes focal adhesion turnover via FAK/paxillin pathway (deep research), but this is downstream of core angiogenic function. Supporting Evidence: PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
GO:0035148 tube formation	IDA PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated...	ACCEPT	Summary: VEGFA is essential for vascular tube formation/tubulogenesis during angiogenesis. Reason: Core function. Deep research extensively documents VEGF role in vasculogenic tubulogenesis and lumen formation. Supporting Evidence: PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
GO:0045766 positive regulation of angiogenesis	IDA PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated...	ACCEPT	Summary: VEGFA is the master regulator of angiogenesis. ISOFORM NOTE - applies to pro-angiogenic isoforms; VEGF165b is anti-angiogenic. Reason: Core function for pro-angiogenic isoforms. Deep research describes VEGFA as "master regulator of angiogenesis." Supporting Evidence: PMID:19033661 AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
GO:0008083 growth factor activity	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: VEGFA is a canonical growth factor inducing cell proliferation via VEGFR2 signaling. Reason: Core molecular function. VEGFA functions as a homodimeric growth factor (PMID:7929439, deep research). Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0035924 cellular response to vascular endothelial growth factor stimulus	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	REMOVE	Summary: Circular annotation - VEGFA IS the stimulus, not the responder. This annotation is logically problematic. Reason: Circular annotation. VEGFA is the stimulus, not a gene responding to VEGF stimulus. This annotation should be on VEGF-responsive genes, not VEGFA itself. Supporting Evidence: PMID:18440775 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
GO:0042056 chemoattractant activity	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: VEGFA is a chemoattractant for endothelial cells and monocytes/macrophages. Reason: Core molecular function. Deep research and PMID:7929439 confirm VEGFA induces chemotaxis in endothelial cells and macrophages. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0050918 positive chemotaxis	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: VEGFA induces positive chemotaxis in endothelial cells and other cell types. Reason: Core biological process. PMID:7929439 shows VEGF induces chemotaxis in KDR-expressing cells. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0005515 protein binding	IPI PMID:22020326 MULTIMERIN2 impairs tumor angiogenesis and growth by interfe...	MARK AS OVER ANNOTATED	Summary: Generic protein binding term is uninformative. VEGFA binds specifically to VEGFRs, neuropilins, heparin, fibronectin. Reason: Uninformative term. More specific terms like VEGFR binding, heparin binding capture the actual binding functions. Generic "protein binding" adds no useful information. Supporting Evidence: PMID:22020326 MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:18093989 Developmental coronary maturation is disturbed by aberrant c...	UNDECIDED	Summary: VEGF signaling can modulate transcription. Publication not in cache for verification. Reason: Publication PMID:18093989 not available in cache. Cannot verify specific transcriptional regulatory mechanism. Supporting Evidence: PMID:18093989 Dec 18. Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling.
GO:0001541 ovarian follicle development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in ovarian follicle development through vascularization. ISS from mouse ortholog. Reason: Pleiotropic developmental process. VEGFA provides vascular support for follicle development but this is secondary to core angiogenic function.
GO:0001701 in utero embryonic development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA essential for embryonic vascular development. ISS from mouse studies showing embryonic lethality. Reason: Pleiotropic developmental process. VEGFA is essential for embryonic development primarily through its role in vascular formation. Deep research notes VEGFR2 null mice die at E8.5.
GO:0001822 kidney development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA important for kidney vascular development. ISS from mouse ortholog. Reason: Pleiotropic developmental process. VEGFA supports kidney development through angiogenesis. Deep research mentions isoform-specific kidney defects.
GO:0002052 positive regulation of neuroblast proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA has neuroprotective and neuroproliferative effects beyond angiogenesis. Reason: Secondary function. VEGFA has documented effects on neural cells but this is not a core function.
GO:0003007 heart morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA essential for cardiac vascular development. ISS from mouse studies. Reason: Pleiotropic developmental process. Deep research notes VEGF-dependent cardiovascular morphogenesis starting at E7.5-8.0 in mice.
GO:0003151 outflow tract morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in cardiac outflow tract development through vascularization. ISS from mouse. Reason: Pleiotropic developmental process. Secondary to core angiogenic function.
GO:0003169 coronary vein morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in coronary vessel development. ISS from mouse studies. Reason: Pleiotropic developmental process. Deep research mentions coronary vein morphogenesis defects in VEGF isoform-specific mice.
GO:0007498 mesoderm development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA expressed during mesodermal development supporting vascular formation. Reason: Pleiotropic developmental process. VEGF is expressed in mesoderm but function is through vascularization.
GO:0007595 lactation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in mammary gland vascularization during lactation. Reason: Pleiotropic physiological process. Secondary to angiogenic function.
GO:0030324 lung development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA essential for lung vascular development. Defects seen in isoform-specific mice. Reason: Pleiotropic developmental process. Deep research notes lung defects in VEGF120/120 mice.
GO:0030855 epithelial cell differentiation	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: VEGFA may affect epithelial differentiation through paracrine effects. Reason: Indirect effect. VEGFA primarily acts on endothelial cells; effects on epithelium are likely secondary/paracrine.
GO:0031077 post-embryonic camera-type eye development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in retinal vascular development. Reason: Pleiotropic developmental process. Deep research notes retinal defects in isoform-specific VEGF mice.
GO:0036303 lymph vessel morphogenesis	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: VEGFA may have limited role in lymphangiogenesis; VEGF-C/VEGFR3 is primary pathway. Reason: VEGF-C and VEGFR3 are the primary lymphangiogenic factors. VEGFA role in lymphangiogenesis is minor compared to its role in blood vessel angiogenesis.
GO:0042462 eye photoreceptor cell development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA may affect photoreceptor development through retinal vascularization. Reason: Pleiotropic developmental process. Likely indirect effect through retinal vascularization.
GO:0043129 surfactant homeostasis	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: VEGFA may affect lung surfactant through pulmonary vascular development. Reason: Indirect effect. This is likely a secondary consequence of VEGFA role in lung vascular development, not a direct function.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:18093989 Developmental coronary maturation is disturbed by aberrant c...	UNDECIDED	Summary: VEGF signaling activates transcription factors that regulate gene expression. Publication not in cache. Reason: Publication PMID:18093989 not available in cache. Cannot verify specific transcriptional mechanism. Supporting Evidence: PMID:18093989 Dec 18. Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling.
GO:0048469 cell maturation	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: VEGFA may affect cell maturation in various tissues through vascularization. Reason: Too general. Cell maturation effects are likely indirect through vascular support.
GO:0048593 camera-type eye morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in eye vascular development. Reason: Pleiotropic developmental process. VEGFA contributes to eye development through vascularization.
GO:0048844 artery morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA essential for arterial vessel development. Reason: Pleiotropic developmental process related to core angiogenic function. Deep research mentions artery defects in isoform-specific mice.
GO:0050679 positive regulation of epithelial cell proliferation	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: VEGFA primarily acts on endothelial cells; epithelial effects are secondary. Reason: Indirect effect. VEGFA primarily stimulates endothelial cell proliferation, not epithelial.
GO:0055013 cardiac muscle cell development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA supports cardiac development through vascularization. Reason: Pleiotropic developmental process. VEGFA affects cardiomyocyte development indirectly through coronary vascularization.
GO:0060319 primitive erythrocyte differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA may affect primitive erythropoiesis during early development. Reason: Pleiotropic developmental process. VEGFA expressed in yolk sac during primitive hematopoiesis.
GO:0060749 mammary gland alveolus development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA supports mammary gland development through vascularization. Reason: Pleiotropic developmental process. Indirect effect through vascular support.
GO:0060948 cardiac vascular smooth muscle cell development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in coronary vascular smooth muscle development. Reason: Pleiotropic developmental process related to cardiac vascular development.
GO:0060982 coronary artery morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA essential for coronary artery development. Reason: Pleiotropic developmental process. Deep research mentions coronary artery defects in isoform-specific mice.
GO:0071542 dopaminergic neuron differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA has neuroprotective effects but primary function is angiogenic. Reason: Secondary function. VEGFA has documented neurotrophic effects but this is not core function.
GO:0090190 positive regulation of branching involved in ureteric bud morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA involved in kidney/ureteric bud development through vascularization. Reason: Pleiotropic developmental process. Effect on ureteric bud likely through supporting vascularization.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:16489009 Minimal active domain and mechanism of action of the angioge...	ACCEPT	Summary: VEGFA stimulates endothelial cell proliferation. Core function for pro-angiogenic isoforms. Reason: Core function. Multiple lines of evidence support VEGFA-induced endothelial proliferation through VEGFR2 signaling. Supporting Evidence: PMID:16489009 Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein.
GO:0051894 positive regulation of focal adhesion assembly	IDA PMID:16489009 Minimal active domain and mechanism of action of the angioge...	KEEP AS NON CORE	Summary: VEGFA signaling promotes focal adhesion assembly during endothelial cell migration. Reason: Supporting function for cell migration. Deep research notes FAK/paxillin pathway involvement. Supporting Evidence: PMID:16489009 Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein.
GO:0002042 cell migration involved in sprouting angiogenesis	IDA PMID:20660291 Gremlin is a novel agonist of the major proangiogenic recept...	ACCEPT	Summary: VEGFA is essential for endothelial cell migration during sprouting angiogenesis. Reason: Core function. Deep research extensively documents VEGF role in sprouting angiogenesis and directed endothelial migration. Supporting Evidence: PMID:20660291 2010 Jul 21. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
GO:0002092 positive regulation of receptor internalization	IDA PMID:20660291 Gremlin is a novel agonist of the major proangiogenic recept...	KEEP AS NON CORE	Summary: VEGF binding induces VEGFR2 internalization as part of signaling. Reason: Part of VEGFR2 signaling mechanism. Deep research notes neuropilin-1 guides VEGFR2 internalization and recycling. Supporting Evidence: PMID:20660291 2010 Jul 21. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
GO:0043184 vascular endothelial growth factor receptor 2 binding	IPI PMID:20660291 Gremlin is a novel agonist of the major proangiogenic recept...	ACCEPT	Summary: VEGFA binds VEGFR2 (KDR) to activate angiogenic signaling. Core molecular function. Reason: Core molecular function. Deep research and multiple publications confirm VEGFA-VEGFR2 binding. Supporting Evidence: PMID:20660291 gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
GO:0048018 receptor ligand activity	IPI PMID:20660291 Gremlin is a novel agonist of the major proangiogenic recept...	ACCEPT	Summary: VEGFA functions as a ligand for VEGFR1 and VEGFR2 receptors. Reason: Core molecular function. VEGFA is the canonical ligand for VEGF receptors. Supporting Evidence: PMID:20660291 2010 Jul 21. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
GO:0005737 cytoplasm	IDA PMID:17082651 Expression and functions of the vascular endothelial growth ...	KEEP AS NON CORE	Summary: VEGFA is synthesized in cytoplasm before secretion. Deep research notes intracrine VEGF signaling. Reason: Cellular component for synthesis. Primary functional location is extracellular but intracrine signaling also documented. Supporting Evidence: PMID:17082651 Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.
GO:0030141 secretory granule	IDA PMID:17082651 Expression and functions of the vascular endothelial growth ...	KEEP AS NON CORE	Summary: VEGFA is stored in secretory granules before release. Reason: Part of secretory pathway. Deep research notes VEGF trafficking through secretory pathway and plasma membrane localization. Supporting Evidence: PMID:17082651 Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.
GO:0042056 chemoattractant activity	IDA PMID:21245381 Neuropilin-1 signaling through p130Cas tyrosine phosphorylat...	ACCEPT	Summary: VEGFA is a chemoattractant for endothelial cells and macrophages. Reason: Core molecular function. Multiple independent IDA annotations confirm chemoattractant activity. Supporting Evidence: PMID:21245381 Jan 18. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.
GO:0045766 positive regulation of angiogenesis	IDA PMID:20497126 Characterization of the biological effects of a novel protei...	ACCEPT	Summary: VEGFA is the master regulator of angiogenesis. ISOFORM NOTE - applies to pro-angiogenic isoforms. Reason: Core biological process. Consistent with other IDA evidence for this term. Supporting Evidence: PMID:20497126 Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:18059339 The zinc-finger transcription factor, early growth response ...	KEEP AS NON CORE	Summary: VEGF signaling activates transcription factors including those regulating gene expression. Reason: Downstream effect of VEGF signaling. VEGF activates ERK/MAPK which translocates to nucleus and activates transcription. Supporting Evidence: PMID:18059339 Dec 3. The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis.
GO:0005125 cytokine activity	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	KEEP AS NON CORE	Summary: VEGFA has cytokine-like activity influencing immune cells via VEGFR1. Reason: Secondary function. VEGFA affects macrophage polarization but primary function is growth factor activity. Supporting Evidence: PMID:18440775 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
GO:0038091 positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway	IDA PMID:17470632 Vascular endothelial growth factor can signal through platel...	MARK AS OVER ANNOTATED	Summary: VEGFA can cross-activate PDGFR signaling. Overly specific term. Reason: Overly specific/contorted term. VEGFA primarily signals through VEGFRs; PDGFR cross-talk is minor. Supporting Evidence: PMID:17470632 Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
GO:0042056 chemoattractant activity	IDA PMID:18440775 Vascular endothelial growth factor induces heat shock protei...	ACCEPT	Summary: VEGFA is a chemoattractant. Duplicate annotation with different reference. Reason: Core molecular function. Consistent with other chemoattractant annotations. Supporting Evidence: PMID:18440775 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis	IDA PMID:20551324 Erk5 activation elicits a vasoprotective endothelial phenoty...	ACCEPT	Summary: VEGFA promotes endothelial cell migration during sprouting angiogenesis. Reason: Core function. Specific to sprouting angiogenesis, a key VEGFA-dependent process. Supporting Evidence: PMID:20551324 2010 Jun 15. Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Kruppel-like factor 4 (KLF4).
GO:0030224 monocyte differentiation	IDA PMID:21149635 Monocytic cells derived from human embryonic stem cells and ...	KEEP AS NON CORE	Summary: VEGFA affects monocyte differentiation via VEGFR1 signaling. Reason: Secondary function. VEGFA affects immune cells but this is not a core function. Supporting Evidence: PMID:21149635 2010 Dec 13. Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions.
GO:0030225 macrophage differentiation	IDA PMID:21149635 Monocytic cells derived from human embryonic stem cells and ...	KEEP AS NON CORE	Summary: VEGFA promotes M2 macrophage polarization via VEGFR1. Reason: Secondary function. Deep research documents VEGF promotion of M2 polarization but this is not core. Supporting Evidence: PMID:21149635 2010 Dec 13. Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions.
GO:0005172 vascular endothelial growth factor receptor binding	IPI PMID:10471394 Characterization of the VEGF binding site on the Flt-1 recep...	ACCEPT	Summary: VEGFA binds to VEGFR1 (Flt-1). Core molecular function. Reason: Core molecular function. Multiple references confirm VEGFR binding. Supporting Evidence: PMID:10471394 Characterization of the VEGF binding site on the Flt-1 receptor.
GO:0005172 vascular endothelial growth factor receptor binding	IPI PMID:11513746 Direct identification of a major autophosphorylation site on...	ACCEPT	Summary: VEGFA binds to VEGFRs. Duplicate with different reference. Reason: Core molecular function. Additional reference supporting VEGFR binding. Supporting Evidence: PMID:11513746 Direct identification of a major autophosphorylation site on vascular endothelial growth factor receptor Flt-1 that mediates phosphatidylinositol 3'-kinase binding.
GO:0045785 positive regulation of cell adhesion	IDA PMID:19674970 Critical role for GATA3 in mediating Tie2 expression and fun...	KEEP AS NON CORE	Summary: VEGFA promotes cell adhesion, supporting endothelial migration and vessel formation. Reason: Supporting function for angiogenesis. Part of cell migration machinery. Supporting Evidence: PMID:19674970 2009 Aug 12. Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:12714610 Expression and localization of tenomodulin, a transmembrane ...	ACCEPT	Summary: VEGFA stimulates endothelial proliferation. Multiple independent references. Reason: Core function. Consistent with other IDA annotations. Supporting Evidence: PMID:12714610 Expression and localization of tenomodulin, a transmembrane type chondromodulin-I-related angiogenesis inhibitor, in mouse eyes.
GO:0042056 chemoattractant activity	IDA PMID:17082651 Expression and functions of the vascular endothelial growth ...	ACCEPT	Summary: VEGFA is a chemoattractant. Additional independent reference. Reason: Core molecular function. Consistent evidence across multiple publications. Supporting Evidence: PMID:17082651 Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:10022831 Role of alphavbeta3 integrin in the activation of vascular e...	ACCEPT	Summary: VEGFA stimulates endothelial proliferation through VEGFR2. Reason: Core function. Additional independent IDA evidence. Supporting Evidence: PMID:10022831 Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.
GO:0010595 positive regulation of endothelial cell migration	IDA PMID:10022831 Role of alphavbeta3 integrin in the activation of vascular e...	ACCEPT	Summary: VEGFA promotes endothelial cell migration through integrin-VEGFR2 cooperation. Reason: Core function. The cited paper is about integrin alphavbeta3 and VEGFR2 activation. Supporting Evidence: PMID:10022831 Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.
GO:0043184 vascular endothelial growth factor receptor 2 binding	IPI PMID:10022831 Role of alphavbeta3 integrin in the activation of vascular e...	ACCEPT	Summary: VEGFA binds VEGFR2/KDR. Paper about integrin-VEGFR2 activation. Reason: Core molecular function. Multiple references confirm VEGFA-VEGFR2 binding. Supporting Evidence: PMID:10022831 Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.
GO:0045766 positive regulation of angiogenesis	IMP PMID:18275976 Aquaporin 1 is required for hypoxia-inducible angiogenesis i...	ACCEPT	Summary: VEGFA promotes angiogenesis. IMP evidence adds to existing support. Reason: Core function. Multiple lines of evidence support this annotation. Supporting Evidence: PMID:18275976 2008 Jan 3. Aquaporin 1 is required for hypoxia-inducible angiogenesis in human retinal vascular endothelial cells.
GO:0071456 cellular response to hypoxia	IDA PMID:10575000 Placenta growth factor and vascular endothelial growth facto...	KEEP AS NON CORE	Summary: VEGFA expression is induced by hypoxia and mediates cellular hypoxic response. Reason: VEGFA is induced BY hypoxia rather than being a direct responder. This describes regulation of VEGFA rather than its function. Supporting Evidence: PMID:10575000 Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:18577655 The effects of growth factors on the proliferation and in vi...	ACCEPT	Summary: VEGFA stimulates endothelial proliferation. Additional IDA evidence. Reason: Core function. Consistent with multiple other IDA annotations. Supporting Evidence: PMID:18577655 The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells.
GO:0045766 positive regulation of angiogenesis	IDA PMID:18577655 The effects of growth factors on the proliferation and in vi...	ACCEPT	Summary: VEGFA is master regulator of angiogenesis. Additional IDA support. Reason: Core function. Consistent evidence across publications. Supporting Evidence: PMID:18577655 The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells.
GO:0001938 positive regulation of endothelial cell proliferation	ISS GO_REF:0000024	ACCEPT	Summary: VEGFA stimulates endothelial proliferation. ISS from ortholog. Reason: Core function. Supported by multiple IDA annotations for human.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growt...	ACCEPT	Summary: VEGFA stimulates endothelial proliferation. Additional IDA evidence. Reason: Core function. Consistent with multiple other annotations. Supporting Evidence: PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
GO:0001968 fibronectin binding	IDA PMID:14570917 pH regulates vascular endothelial growth factor binding to f...	ACCEPT	Summary: VEGFA binds fibronectin in the extracellular matrix for storage/presentation. Reason: Functional binding. Deep research notes VEGF binds ECM for storage and controlled release. Supporting Evidence: PMID:14570917 2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.
GO:0002687 positive regulation of leukocyte migration	TAS PMID:1312256 The fms-like tyrosine kinase, a receptor for vascular endoth...	KEEP AS NON CORE	Summary: VEGFA promotes leukocyte/monocyte migration through VEGFR1. Reason: Secondary function. VEGFA is chemoattractant for monocytes/macrophages but primary function is angiogenic. Supporting Evidence: PMID:1312256 The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
GO:0005125 cytokine activity	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: VEGFA has cytokine-like functions affecting immune cells. Reason: Secondary function. VEGFA is primarily a growth factor; cytokine activity is secondary.
GO:0005615 extracellular space	ISS GO_REF:0000024	ACCEPT	Summary: VEGFA is secreted and functions in extracellular space. Reason: Core cellular component. VEGFA is a secreted growth factor acting extracellularly.
GO:0005615 extracellular space	IDA PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growt...	ACCEPT	Summary: VEGFA is secreted and detected in extracellular space. Reason: Core cellular component. IDA evidence confirms extracellular localization. Supporting Evidence: PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
GO:0008083 growth factor activity	ISS GO_REF:0000024	ACCEPT	Summary: VEGFA is a canonical growth factor. ISS from ortholog. Reason: Core molecular function. Supported by extensive IDA evidence.
GO:0008083 growth factor activity	IDA PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growt...	ACCEPT	Summary: VEGFA is a canonical growth factor stimulating cell proliferation. Reason: Core molecular function. Multiple IDA annotations confirm growth factor activity. Supporting Evidence: PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
GO:0008201 heparin binding	IMP PMID:14570917 pH regulates vascular endothelial growth factor binding to f...	ACCEPT	Summary: VEGF isoforms differ in heparin binding affinity. VEGF165 has intermediate, VEGF189/206 high binding. Reason: Core molecular function for ECM-binding isoforms. Deep research documents isoform-specific heparin binding. Supporting Evidence: PMID:14570917 2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.
GO:0008284 positive regulation of cell population proliferation	IDA PMID:7929439 Different signal transduction properties of KDR and Flt1, tw...	ACCEPT	Summary: VEGFA stimulates cell proliferation through VEGFR2 signaling. Reason: Core function. PMID:7929439 demonstrates mitogenic activity in KDR-expressing cells. Supporting Evidence: PMID:7929439 The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
GO:0008360 regulation of cell shape	IDA PMID:10527820 The effects of angiogenic growth factors on extravillous tro...	KEEP AS NON CORE	Summary: VEGFA induces morphological changes in endothelial cells during migration. Reason: Part of migration response. Cell shape changes support angiogenic cell migration. Supporting Evidence: PMID:10527820 The effects of angiogenic growth factors on extravillous trophoblast invasion and motility.
GO:0008360 regulation of cell shape	IDA PMID:7929439 Different signal transduction properties of KDR and Flt1, tw...	KEEP AS NON CORE	Summary: VEGFA induces striking morphological changes via VEGFR2/KDR. Reason: Part of migration response. PMID:7929439 describes actin reorganization and membrane ruffling. Supporting Evidence: PMID:7929439 The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
GO:0030335 positive regulation of cell migration	IDA PMID:7929439 Different signal transduction properties of KDR and Flt1, tw...	ACCEPT	Summary: VEGFA promotes cell migration/chemotaxis through VEGFR2/KDR. Reason: Core function. PMID:7929439 demonstrates chemotaxis in KDR-expressing cells. Supporting Evidence: PMID:7929439 The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
GO:0043183 vascular endothelial growth factor receptor 1 binding	IPI PMID:1312256 The fms-like tyrosine kinase, a receptor for vascular endoth...	ACCEPT	Summary: VEGFA binds VEGFR1/Flt-1 with high affinity but weak signaling. Reason: Core molecular function. Deep research confirms VEGFA-VEGFR1 binding with Kd ~16 pM. Supporting Evidence: PMID:1312256 The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
GO:0043184 vascular endothelial growth factor receptor 2 binding	IPI PMID:1417831 Identification of the KDR tyrosine kinase as a receptor for ...	ACCEPT	Summary: VEGFA binds VEGFR2/KDR as the main pro-angiogenic receptor. Reason: Core molecular function. VEGFR2 is the primary angiogenic signaling receptor. Supporting Evidence: PMID:1417831 Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor.
GO:0043536 positive regulation of blood vessel endothelial cell migration	IDA PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growt...	ACCEPT	Summary: VEGFA promotes endothelial cell migration, essential for angiogenesis. Reason: Core function. More specific than general cell migration term. Supporting Evidence: PMID:9202027 Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
GO:0050840 extracellular matrix binding	IC PMID:14570917 pH regulates vascular endothelial growth factor binding to f...	ACCEPT	Summary: VEGF binds ECM components including fibronectin and heparan sulfate proteoglycans. Reason: Functional binding. Deep research documents ECM binding for VEGF storage and controlled release. Supporting Evidence: PMID:14570917 2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.
GO:0050927 positive regulation of positive chemotaxis	IDA PMID:12744932 Vascular endothelial growth factor is a chemoattractant for ...	ACCEPT	Summary: VEGFA induces positive chemotaxis in trophoblast and endothelial cells. Reason: Core function. VEGFA is a well-established chemoattractant. Supporting Evidence: PMID:12744932 Vascular endothelial growth factor is a chemoattractant for trophoblast cells.
GO:0050927 positive regulation of positive chemotaxis	IDA PMID:7929439 Different signal transduction properties of KDR and Flt1, tw...	ACCEPT	Summary: VEGFA induces chemotaxis through VEGFR2/KDR. Reason: Core function. PMID:7929439 demonstrates chemotaxis in KDR-expressing cells. Supporting Evidence: PMID:7929439 Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.
GO:0005161 platelet-derived growth factor receptor binding	IPI PMID:17470632 Vascular endothelial growth factor can signal through platel...	MARK AS OVER ANNOTATED	Summary: VEGFA may have some PDGFR cross-reactivity. Reason: Minor cross-talk. VEGFA primarily binds VEGFRs; PDGFR binding is not a core function. Supporting Evidence: PMID:17470632 Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
GO:0009986 cell surface	IDA PMID:17470632 Vascular endothelial growth factor can signal through platel...	KEEP AS NON CORE	Summary: VEGFA can localize to cell surface. Deep research notes plasma membrane localization. Reason: Part of secretory pathway. VEGFA is found on cell surface before release. Supporting Evidence: PMID:17470632 Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
GO:0030335 positive regulation of cell migration	IDA PMID:17470632 Vascular endothelial growth factor can signal through platel...	ACCEPT	Summary: VEGFA promotes cell migration. Additional independent reference. Reason: Core function. Consistent with multiple other annotations. Supporting Evidence: PMID:17470632 Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
GO:0001666 response to hypoxia	IDA PMID:16490744 Hypoxic conditions stimulate the production of angiogenin an...	KEEP AS NON CORE	Summary: VEGFA expression is induced by hypoxia via HIF-1. This annotation describes VEGFA regulation. Reason: Describes regulation of VEGFA rather than VEGFA function. VEGFA is a hypoxia-responsive gene. Supporting Evidence: PMID:16490744 2006 Feb 20. Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.
GO:0005615 extracellular space	IDA PMID:16490744 Hypoxic conditions stimulate the production of angiogenin an...	ACCEPT	Summary: VEGFA is secreted into extracellular space. Reason: Core cellular component. VEGFA functions as an extracellular signaling molecule. Supporting Evidence: PMID:16490744 2006 Feb 20. Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.
GO:0001525 angiogenesis	IDA PMID:11427521 Vascular endothelial growth factor induces cyclooxygenase-de...	ACCEPT	Summary: VEGFA is essential for angiogenesis. Reason: Core biological process. VEGFA is the master regulator of angiogenesis. Supporting Evidence: PMID:11427521 Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor.
GO:0001570 vasculogenesis	TAS PMID:15015550 Vasculogenesis and angiogenesis.	ACCEPT	Summary: VEGFA is essential for de novo blood vessel formation from vascular progenitors. Reason: Core biological process. Deep research documents VEGF role in vasculogenesis. Supporting Evidence: PMID:15015550 Vasculogenesis and angiogenesis.
GO:0007399 nervous system development	TAS PMID:15351965 VEGF: once regarded as a specific angiogenic factor, now imp...	KEEP AS NON CORE	Summary: VEGFA has neurotrophic/neuroprotective effects beyond angiogenesis. Reason: Secondary function. VEGFA affects neural development but primary function is angiogenic. Supporting Evidence: PMID:15351965 VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection.
GO:0008201 heparin binding	IDA PMID:15001987 Heparin affin regulatory peptide binds to vascular endotheli...	ACCEPT	Summary: VEGF binds heparin. Isoform-specific binding affinity. Reason: Core molecular function. Multiple independent references confirm heparin binding. Supporting Evidence: PMID:15001987 Heparin affin regulatory peptide binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis.
GO:0031012 extracellular matrix	NAS PMID:14570917 pH regulates vascular endothelial growth factor binding to f...	ACCEPT	Summary: VEGF localizes to extracellular matrix especially longer isoforms. Reason: Functional localization. VEGF189/206 are matrix-bound; matrix serves as VEGF reservoir. Supporting Evidence: PMID:14570917 2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.
GO:0043066 negative regulation of apoptotic process	IMP PMID:10066377 VEGF prevents apoptosis of human microvascular endothelial c...	ACCEPT	Summary: VEGFA promotes endothelial cell survival through PI3K-Akt pathway. Reason: Core function for endothelial cell survival. Deep research documents Akt-mediated anti-apoptotic signaling. Supporting Evidence: PMID:10066377 VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling.
GO:0050930 induction of positive chemotaxis	NAS PMID:12744932 Vascular endothelial growth factor is a chemoattractant for ...	ACCEPT	Summary: NAS evidence for chemotaxis. Consistent with IBA and other evidence. Reason: Core biological process. VEGFA induces chemotaxis in multiple cell types. Supporting Evidence: PMID:12744932 Vascular endothelial growth factor is a chemoattractant for trophoblast cells.
GO:0016525 negative regulation of angiogenesis	IDA file:human/VEGFA/VEGFA-deep-research-perplexity.md	NEW	Summary: CRITICAL: The VEGF165B isoform (P15692-8) is ANTI-ANGIOGENIC. It binds VEGFR2 but fails to activate downstream signaling, acting as an endogenous inhibitor of angiogenesis. VEGF165B inhibits VEGF165-induced proliferation, migration, and vasodilatation. In colon carcinoma, VEGF165B inhibits tumor growth by blocking angiogenesis. This function is NOT captured by any existing GOA annotation. Reason: Critical missing annotation. VEGF165B has opposite biological activity to other isoforms. The deep research documents that VEGF165B has anti-angiogenic properties and inhibits tumor growth. This represents a fundamentally different function from the pro-angiogenic isoforms currently annotated.

Core Functions

VEGFA binds to VEGFR1 (FLT1), VEGFR2 (KDR), and co-receptors including neuropilins. This is the primary molecular function enabling all downstream signaling. All isoforms bind receptors, though VEGF165B binding does not activate signaling.

Molecular Function:

vascular endothelial growth factor receptor binding

Directly Involved In:

vascular endothelial growth factor receptor signaling pathway positive regulation of angiogenesis

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:7929439
Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR.

VEGFA is a canonical growth factor stimulating endothelial cell proliferation through VEGFR2-PLCgamma-PKC-MAPK signaling. ISOFORM NOTE: Pro-angiogenic isoforms only; VEGF165B lacks mitogenic activity.

Molecular Function:

growth factor activity

Directly Involved In:

positive regulation of cell population proliferation angiogenesis

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:21771332
50 ng/mL VEGF stimulated HUVEC proliferation by 27% relative to untreated cells.

VEGFA is a chemoattractant for endothelial cells (directing sprouting angiogenesis) and for monocytes/macrophages (via VEGFR1). Essential for guided vessel growth and inflammatory cell recruitment.

Molecular Function:

chemoattractant activity

Directly Involved In:

angiogenesis positive regulation of cell migration

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:7929439
The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

file:human/VEGFA/VEGFA-deep-research-perplexity.md

Deep research summary for VEGFA from Perplexity

PMID:10022831

Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.

PMID:10066377

VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling.

PMID:10471394

Characterization of the VEGF binding site on the Flt-1 receptor.

PMID:10527820

The effects of angiogenic growth factors on extravillous trophoblast invasion and motility.

PMID:10543948

Solution structure of the VEGF-binding domain of Flt-1: comparison of its free and bound states.

PMID:10575000

Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes. Implication in autocrine and paracrine regulation of angiogenesis.

PMID:11427521

Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor.

PMID:11461089

Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells.

PMID:11513746

Direct identification of a major autophosphorylation site on vascular endothelial growth factor receptor Flt-1 that mediates phosphatidylinositol 3'-kinase binding.

PMID:12207021

The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor.

PMID:12714610

Expression and localization of tenomodulin, a transmembrane type chondromodulin-I-related angiogenesis inhibitor, in mouse eyes.

PMID:12744932

Vascular endothelial growth factor is a chemoattractant for trophoblast cells.

PMID:1312256

The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.

PMID:1417831

Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor.

PMID:14570917

pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.

PMID:15001987

Heparin affin regulatory peptide binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis.

PMID:15015550

Vasculogenesis and angiogenesis.

PMID:15351965

VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection.

PMID:16150726

Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner.

PMID:16489009

Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein.

PMID:16490744

Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.

PMID:16763549

Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.

PMID:17082651

Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.

PMID:17222790

Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth.

PMID:17446437

Association of ATP1A1 and dear single-nucleotide polymorphism haplotypes with essential hypertension: sex-specific and haplotype-specific effects.

PMID:17470632

Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.

PMID:18059339

The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis.

PMID:18093989

Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling.

PMID:18275976

Aquaporin 1 is required for hypoxia-inducible angiogenesis in human retinal vascular endothelial cells.

PMID:18440775

Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.

PMID:18577655

The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells.

PMID:19033661

AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.

PMID:19148554

Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.

PMID:19652095

Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor.

PMID:19674970

Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells.

PMID:20048167

Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers.

PMID:20123964

Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.

PMID:20497126

Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.

PMID:20551324

Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Kruppel-like factor 4 (KLF4).

PMID:20660291

Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.

PMID:21149635

Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions.

PMID:21245381

Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.

PMID:21653826

VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation.

PMID:21771332

Glioblastoma-derived leptin induces tube formation and growth of endothelial cells: comparison with VEGF effects.

PMID:22020326

MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway.

PMID:23083510

miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.

PMID:23374253

Endorepellin laminin-like globular 1/2 domains bind Ig3-5 of vascular endothelial growth factor (VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells.

PMID:23583373

Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity.

PMID:23688497

MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.

PMID:23878390

MicroRNA 329 suppresses angiogenesis by targeting CD146.

PMID:24844779

Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.

PMID:24865854

Dysregulated miR-361-5p/VEGF axis in the plasma and endothelial progenitor cells of patients with coronary artery disease.

PMID:25132001

Development of a highly-potent anti-angiogenic VEGF8-109 heterodimer by directed blocking of its VEGFR-2 binding site.

PMID:25251394

MicroRNA-377 regulates mesenchymal stem cell-induced angiogenesis in ischemic hearts by targeting VEGF.

PMID:25825981

EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.

PMID:26268439

p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.

PMID:26299712

High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.

PMID:26598555

VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.

PMID:26683794

Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes.

PMID:28977001

MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2.

PMID:30106099

Overexpression of miR‑21 is involved in acute monocytic leukemia‑associated angiogenesis by targeting IL‑12.

PMID:31915155

PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:7929439

Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.

PMID:9202027

Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.

PMID:9393862

Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.

Reactome:R-HSA-1235037

Expression of VEGFA

Reactome:R-HSA-194310

VEGF-A,C,D bind to VEGFR2 leading to receptor dimerization

Reactome:R-HSA-194311

VEGFA,B,PLGF bind to VEGFR1 leading to receptor dimerization

Reactome:R-HSA-195378

Homodimerization of VEGF proteins

Reactome:R-HSA-4420083

PTK2 binds p-S-SHB and is recruited to p-6Y-VEGFR2

Reactome:R-HSA-4420099

p-6Y-VEGFR2 binds SHB

Reactome:R-HSA-4420107

p-6Y-VEGFR2 binds SHC-transforming protein 2

Reactome:R-HSA-4420117

VEGFR2 autophosphorylates

Reactome:R-HSA-4420121

SFKs phosphorylate PLCG1

Reactome:R-HSA-4420128

SRC-1 phosphorylates SHB

Reactome:R-HSA-4420140

SRC1-1 binds SH2D2A and is recruited to VEGFR2

Reactome:R-HSA-4420143

p-6Y-VEGFR2 binds SH2D2A

Reactome:R-HSA-4420153

p-6Y-VEGFR2 binds PLCG1

Reactome:R-HSA-4420202

PLCG1 disassociates from VEGFR2 and translocate to PM

Reactome:R-HSA-4420206

Phosphorylation of SRC-1

Reactome:R-HSA-481007

Exocytosis of platelet alpha granule contents

Reactome:R-HSA-5218640

SRC-1 phosphorylates p-Y397-PTK2

Reactome:R-HSA-5218642

PTK2 autophosphorylates

Reactome:R-HSA-5218643

HSP90AA1 binds p-6Y-VEGFR2

Reactome:R-HSA-5218645

SRC-1 binds p-Y397-PTK2

Reactome:R-HSA-5218804

p38 MAPK activation by VEGFR

Reactome:R-HSA-5218806

FYN autophosphorylates

Reactome:R-HSA-5218809

PTK2 and SRC-1 phosphorylate PXN on Y31 and Y118

Reactome:R-HSA-5218811

DOCK180:ELMO binds CRK

Reactome:R-HSA-5218812

FYN phosphorylates PAK2

Reactome:R-HSA-5218814

PAK2 autophorylates

Reactome:R-HSA-5218815

p-6Y-VEGFR2 binds NCK

Reactome:R-HSA-5218818

Integrin alphaVbeta3 binds p-6Y-VEGFR2

Reactome:R-HSA-5218819

VEGFA dimer:p-6Y-VEGFR2 dimer:PI3K phosphorylates PIP2 to PIP3

Reactome:R-HSA-5218820

Src kinases phosphorylate VAV

Reactome:R-HSA-5218822

CRK binds BCAR1 and or PXN

Reactome:R-HSA-5218824

p-6Y-VEGFR2 binds FYN

Reactome:R-HSA-5218826

Active ROCK1,ROCK2 phosphorylates p-5Y-PTK2 on S732

Reactome:R-HSA-5218830

SRC-1 phosphorylates PTK2-beta

Reactome:R-HSA-5218832

CDC42:GTP binds PAK2

Reactome:R-HSA-5218836

PTK2beta binds alphaVbeta3

Reactome:R-HSA-5218838

PXN binds p-6Y,S732-PTK2

Reactome:R-HSA-5218839

DOCK180:ELMO exchanges GTP for GDP, activating RAC1

Reactome:R-HSA-5218847

PAK2 binds NCK

Reactome:R-HSA-5218851

p-Y402-PTK2B phosphorylates p-5Y,S732-PTK2 on Y407

Reactome:R-HSA-5218854

p-Y420-FYN is phosphorylated on S21

Reactome:R-HSA-5357429

AXL autophosphorylates on Y779 and Y821

Reactome:R-HSA-5357432

AXL binds SRC-1

Reactome:R-HSA-5357479

p-AXL binds PI3K

Reactome:R-HSA-6789615

Expression of STAT3-upregulated extracellular proteins

Reactome:R-HSA-8864936

VEGFA gene expression is inhibited by the TFAP2A homodimer

Reactome:R-HSA-9679477

VEGFA-165 dimer binds VEGFA inhibitors

Reactome:R-HSA-9691215

VEGFA-165 dimer binds VEGFR2 dimer

📚 Additional Documentation

Deep Research Bioreason

(VEGFA-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:55 AM

Organism: Homo sapiens

Sequence:

MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGCSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR

Thinking Trace

I begin with the InterPro architecture and its order along the polypeptide. A broad family signature, IPR050507 (Platelet-derived/Vascular endothelial growth factor family, residues 154–395), spans the C-terminal half of the protein and frames the overall identity as a secreted growth factor of the PDGF/VEGF lineage. Nested within this, IPR029034 (Cystine-knot cytokine homologous superfamily, residues 215–327) and IPR000072 (PDGF/VEGF domain, residues 219–315) define the canonical cystine-knot fold that obligately forms disulfide-stabilized dimers. This fold imposes high structural rigidity and creates receptor-binding surfaces typical of receptor tyrosine kinase ligands. The conserved functional patch marked by IPR023581 (Platelet-derived growth factor, conserved site, residues 255–267) further specifies the signaling-competent interface that couples to endothelial receptors. Distal to the core cystine-knot, the C-terminal tail carries IPR036841 (VEGF heparin-binding domain superfamily, residues 342–395) and its concrete instantiation IPR027928 (VEGF heparin-binding domain, residues 346–395). This basic, glycosaminoglycan-binding module causes avid interactions with cell-surface heparan sulfate proteoglycans and extracellular matrix, which concentrate and localize the ligand to pericellular niches and basement membranes.

This ordered arrangement dictates molecular function. The cystine-knot PDGF/VEGF core and conserved receptor-contact site generate high-affinity signaling receptor engagement; thus the molecule operates as a growth factor that binds and activates endothelial receptor tyrosine kinases. The heparin-binding appendage amplifies this by tethering the ligand to sulfated matrices and co-receptors, enhancing receptor clustering and signal potency. Together these features specify GO:0008083 growth factor activity as the molecular function.

From this signaling chemistry, the biological process follows. A VEGF-class ligand drives endothelial proliferation, migration, and permeability programs that construct and remodel capillary beds. By locally concentrating and presenting the ligand via its heparin-binding domain, the protein initiates receptor pathways that culminate in vessel sprouting and stabilization, which is the essence of GO:0001525 angiogenesis.

Cellular location is determined by secretion and matrix tethering. The presence of a signal peptide (implied by the secreted status) and the absence of transmembrane domains place the protein in the extracellular milieu. The heparin-binding domain then enforces retention at the extracellular space and matrix, consistent with a soluble factor that accumulates at basement membranes. This supports localization to the extracellular region and extracellular space.

Mechanistically, I propose that the cystine-knot dimer forms the active signaling unit that binds endothelial receptor tyrosine kinases, most plausibly VEGF receptor isoforms, while the C-terminal heparin-binding tail recruits heparan sulfate proteoglycans to build high-avidity ligand–glycan–receptor assemblies. This architecture causes potent, localized signaling that promotes angiogenic programs. Likely interaction partners therefore include VEGF receptors and cell-surface glycosaminoglycans; additional associations with extracellular matrix components would further stabilize signaling microdomains.

Functional Summary

A secreted human growth factor that adopts a cystine‑knot architecture to signal as a high‑affinity ligand for endothelial receptor tyrosine kinases. By forming a disulfide‑stabilized dimer and using a C‑terminal glycosaminoglycan‑binding tail, it concentrates at the extracellular matrix and basement membranes, where it potently drives endothelial signaling pathways that promote blood vessel formation and remodeling.

UniProt Summary

Growth factor most probably involved in the regulation of angiogenesis.

InterPro Domains

Platelet-derived/Vascular endothelial growth factor (IPR050507, family) — residues 154-395
Cystine-knot cytokine (IPR029034, homologous_superfamily) — residues 215-327
PDGF/VEGF domain (IPR000072, domain) — residues 219-315
Platelet-derived growth factor, conserved site (IPR023581, conserved_site) — residues 255-267
Vascular endothelial growth factor, heparin-binding domain superfamily (IPR036841, homologous_superfamily) — residues 342-395
Vascular endothelial growth factor, heparin-binding domain (IPR027928, domain) — residues 346-395

GO Terms

Molecular Function: molecular_function (GO:0003674), molecular function regulator activity (GO:0098772), binding (GO:0005488), carbohydrate derivative binding (GO:0097367), molecular function activator activity (GO:0140677), extracellular matrix binding (GO:0050840), signaling receptor regulator activity (GO:0030545), sulfur compound binding (GO:1901681), protein binding (GO:0005515), heparin binding (GO:0008201), signaling receptor binding (GO:0005102), glycosaminoglycan binding (GO:0005539), identical protein binding (GO:0042802), fibronectin binding (GO:0001968), signaling receptor activator activity (GO:0030546), growth factor receptor binding (GO:0070851), receptor ligand activity (GO:0048018), cytokine receptor binding (GO:0005126), chemoattractant activity (GO:0042056), cytokine activity (GO:0005125), vascular endothelial growth factor receptor binding (GO:0005172), growth factor activity (GO:0008083)

Biological Process: biological_process (GO:0008150), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), negative regulation of biological process (GO:0048519), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), multicellular organismal process (GO:0032501), developmental process (GO:0032502), cellular process (GO:0009987), locomotion (GO:0040011), homeostatic process (GO:0042592), immune system process (GO:0002376), anatomical structure development (GO:0048856), tissue migration (GO:0090130), positive regulation of multicellular organismal process (GO:0051240), positive regulation of immune system process (GO:0002684), regulation of multicellular organismal process (GO:0051239), multicellular organismal-level homeostasis (GO:0048871), anatomical structure formation involved in morphogenesis (GO:0048646), positive regulation of transport (GO:0051050), negative regulation of metabolic process (GO:0009892), regulation of biological quality (GO:0065008), positive regulation of reproductive process (GO:2000243), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), negative regulation of cellular process (GO:0048523), regulation of locomotion (GO:0040012), response to abiotic stimulus (GO:0009628), cellular developmental process (GO:0048869), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), leukocyte migration (GO:0050900), regulation of molecular function (GO:0065009), cell communication (GO:0007154), positive regulation of cellular process (GO:0048522), response to external stimulus (GO:0009605), anatomical structure morphogenesis (GO:0009653), cell motility (GO:0048870), response to chemical (GO:0042221), regulation of reproductive process (GO:2000241), taxis (GO:0042330), regulation of developmental process (GO:0050793), response to endogenous stimulus (GO:0009719), positive regulation of locomotion (GO:0040017), regulation of signaling (GO:0023051), negative regulation of developmental process (GO:0051093), signal transduction (GO:0007165), positive regulation of signaling (GO:0023056), multicellular organism development (GO:0007275), regulation of localization (GO:0032879), regulation of immune system process (GO:0002682), system process (GO:0003008), positive regulation of metabolic process (GO:0009893), response to stress (GO:0006950), morphogenesis of a branching structure (GO:0001763), positive regulation of developmental process (GO:0051094), response to acid chemical (GO:0001101), negative regulation of cellular component organization (GO:0051129), tube formation (GO:0035148), regulation of cell motility (GO:2000145), regulation of response to stress (GO:0080134), regulation of signal transduction (GO:0009966), regulation of macromolecule metabolic process (GO:0060255), regulation of response to external stimulus (GO:0032101), regulation of vesicle-mediated transport (GO:0060627), regulation of cellular component biogenesis (GO:0044087), regulation of epithelial cell migration (GO:0010632), positive regulation of vasculature development (GO:1904018), leukocyte chemotaxis (GO:0030595), negative regulation of macromolecule metabolic process (GO:0010605), regulation of anatomical structure morphogenesis (GO:0022603), chemotaxis (GO:0006935), positive regulation of nitrogen compound metabolic process (GO:0051173), myeloid leukocyte migration (GO:0097529), regulation of catalytic activity (GO:0050790), negative regulation of nitrogen compound metabolic process (GO:0051172), positive regulation of molecular function (GO:0044093), positive regulation of protein localization (GO:1903829), positive regulation of macromolecule metabolic process (GO:0010604), blood vessel development (GO:0001568), negative regulation of molecular function (GO:0044092), regulation of cellular localization (GO:0060341), regulation of cellular response to stress (GO:0080135), positive regulation of cell motility (GO:2000147), positive regulation of biosynthetic process (GO:0009891), angiogenesis (GO:0001525), regulation of multicellular organismal development (GO:2000026), regulation of cell population proliferation (GO:0042127), regulation of cell death (GO:0010941), positive regulation of cellular metabolic process (GO:0031325), cellular response to stress (GO:0033554), negative regulation of cell differentiation (GO:0045596), regulation of DNA-binding transcription factor activity (GO:0051090), regulation of cellular metabolic process (GO:0031323), positive regulation of cell communication (GO:0010647), negative regulation of biosynthetic process (GO:0009890), regulation of primary metabolic process (GO:0080090), regulation of cellular response to growth factor stimulus (GO:0090287), response to hypoxia (GO:0001666), positive regulation of response to external stimulus (GO:0032103), tissue morphogenesis (GO:0048729), negative regulation of cell death (GO:0060548), regulation of leukocyte migration (GO:0002685), cell development (GO:0048468), cell differentiation (GO:0030154), system development (GO:0048731), response to oxygen levels (GO:0070482), response to growth factor (GO:0070848), regulation of cell adhesion (GO:0030155), cellular response to endogenous stimulus (GO:0071495), positive regulation of cellular component biogenesis (GO:0044089), circulatory system process (GO:0003013), regulation of vascular permeability (GO:0043114), tube development (GO:0035295), negative regulation of cell adhesion (GO:0007162), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cell differentiation (GO:0045595), cell surface receptor signaling pathway (GO:0007166), regulation of cellular component organization (GO:0051128), positive regulation of cell population proliferation (GO:0008284), cell migration (GO:0016477), tube morphogenesis (GO:0035239), positive regulation of signal transduction (GO:0009967), regulation of transport (GO:0051049), response to wounding (GO:0009611), regulation of chemotaxis (GO:0050920), epithelium migration (GO:0090132), morphogenesis of a branching epithelium (GO:0061138), positive regulation of cellular component organization (GO:0051130), positive regulation of cell adhesion (GO:0045785), negative regulation of cellular metabolic process (GO:0031324), anatomical structure homeostasis (GO:0060249), positive regulation of leukocyte migration (GO:0002687), tissue development (GO:0009888), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), regulation of biosynthetic process (GO:0009889), tissue homeostasis (GO:0001894), positive regulation of endocytosis (GO:0045807), positive regulation of chemotaxis (GO:0050921), positive regulation of morphogenesis of an epithelium (GO:1905332), epithelial tube morphogenesis (GO:0060562), granulocyte migration (GO:0097530), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to oxygen levels (GO:0071453), regulation of protein metabolic process (GO:0051246), vasculature development (GO:0001944), regulation of stress-activated protein kinase signaling cascade (GO:0070302), regulation of epithelial cell proliferation (GO:0050678), regulation of gene expression (GO:0010468), positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus (GO:1901522), regulation of endothelial cell migration (GO:0010594), circulatory system development (GO:0072359), response to decreased oxygen levels (GO:0036293), regulation of DNA-templated transcription in response to stress (GO:0043620), positive regulation of cell migration (GO:0030335), positive regulation of intracellular signal transduction (GO:1902533), regulation of leukocyte chemotaxis (GO:0002688), negative regulation of cell-cell adhesion (GO:0022408), positive regulation of catalytic activity (GO:0043085), sprouting angiogenesis (GO:0002040), negative regulation of gene expression (GO:0010629), positive regulation of cell-substrate junction organization (GO:0150117), regulation of vascular endothelial growth factor signaling pathway (GO:1900746), cellular response to hypoxia (GO:0071456), positive regulation of cell junction assembly (GO:1901890), positive regulation of cell-substrate adhesion (GO:0010811), vascular process in circulatory system (GO:0003018), regulation of cell morphogenesis (GO:0022604), enzyme-linked receptor protein signaling pathway (GO:0007167), leukocyte differentiation (GO:0002521), regulation of DNA metabolic process (GO:0051052), regulation of cell development (GO:0060284), negative regulation of protein metabolic process (GO:0051248), regulation of vasculature development (GO:1901342), positive regulation of angiogenesis (GO:0045766), regulation of protein localization (GO:0032880), positive regulation of leukocyte chemotaxis (GO:0002690), myeloid cell differentiation (GO:0030099), ameboidal-type cell migration (GO:0001667), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of RNA metabolic process (GO:0051254), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), positive chemotaxis (GO:0050918), regulation of angiogenesis (GO:0045765), regulation of transferase activity (GO:0051338), epithelium development (GO:0060429), negative regulation of cell development (GO:0010721), cellular response to growth factor stimulus (GO:0071363), positive regulation of cellular biosynthetic process (GO:0031328), positive regulation of protein-containing complex assembly (GO:0031334), regulation of epithelial cell differentiation (GO:0030856), granulocyte chemotaxis (GO:0071621), epithelial cell migration (GO:0010631), cellular response to acid chemical (GO:0071229), regulation of adherens junction organization (GO:1903391), regulation of protein-containing complex assembly (GO:0043254), blood circulation (GO:0008015), negative regulation of programmed cell death (GO:0043069), regulation of cell-substrate adhesion (GO:0010810), regulation of programmed cell death (GO:0043067), regulation of cell-cell adhesion (GO:0022407), positive regulation of vascular permeability (GO:0043117), negative regulation of vascular permeability (GO:0043116), morphogenesis of an epithelium (GO:0002009), positive regulation of receptor-mediated endocytosis (GO:0048260), regulation of cell migration (GO:0030334), regulation of endothelial cell chemotaxis (GO:2001026), regulation of cell-substrate junction organization (GO:0150116), branching morphogenesis of an epithelial tube (GO:0048754), positive regulation of positive chemotaxis (GO:0050927), regulation of morphogenesis of an epithelium (GO:1905330), nervous system development (GO:0007399), branching involved in blood vessel morphogenesis (GO:0001569), vasculogenesis (GO:0001570), negative regulation of cellular biosynthetic process (GO:0031327), regulation of RNA metabolic process (GO:0051252), negative regulation of nucleobase-containing compound metabolic process (GO:0045934), positive regulation of DNA-binding transcription factor activity (GO:0051091), regulation of endocytosis (GO:0030100), hemopoiesis (GO:0030097), regulation of positive chemotaxis (GO:0050926), negative regulation of catalytic activity (GO:0043086), positive regulation of phosphorus metabolic process (GO:0010562), positive regulation of DNA metabolic process (GO:0051054), regulation of hydrolase activity (GO:0051336), regulation of cell junction assembly (GO:1901888), positive regulation of gene expression (GO:0010628), regulation of cellular response to vascular endothelial growth factor stimulus (GO:1902547), cell chemotaxis (GO:0060326), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), wound healing (GO:0042060), blood vessel morphogenesis (GO:0048514), angiogenesis involved in wound healing (GO:0060055), maintenance of blood-brain barrier (GO:0035633), positive regulation of epithelial cell migration (GO:0010634), negative regulation of epithelial cell differentiation (GO:0030857), positive regulation of protein metabolic process (GO:0051247), negative regulation of macromolecule biosynthetic process (GO:0010558), negative regulation of RNA metabolic process (GO:0051253), regulation of intracellular signal transduction (GO:1902531), regulation of phosphorus metabolic process (GO:0051174), regulation of apoptotic process (GO:0042981), regulation of sprouting angiogenesis (GO:1903670), positive regulation of phosphate metabolic process (GO:0045937), regulation of RNA biosynthetic process (GO:2001141), regulation of cell-matrix adhesion (GO:0001952), regulation of endothelial cell differentiation (GO:0045601), regulation of kinase activity (GO:0043549), regulation of protein kinase B signaling (GO:0051896), positive regulation of RNA biosynthetic process (GO:1902680), positive regulation of cell-matrix adhesion (GO:0001954), regulation of transcription from RNA polymerase II promoter in response to stress (GO:0043618), myeloid leukocyte differentiation (GO:0002573), positive regulation of protein modification process (GO:0031401), regulation of stress-activated MAPK cascade (GO:0032872), regulation of cell shape (GO:0008360), regulation of nitric oxide mediated signal transduction (GO:0010749), regulation of MAPK cascade (GO:0043408), regulation of receptor-mediated endocytosis (GO:0048259), positive regulation of endothelial cell proliferation (GO:0001938), positive regulation of transferase activity (GO:0051347), positive regulation of CREB transcription factor activity (GO:0032793), regulation of cell-substrate junction assembly (GO:0090109), negative regulation of proteolysis (GO:0045861), regulation of phosphatidylinositol 3-kinase signaling (GO:0014066), negative regulation of hydrolase activity (GO:0051346), regulation of proteolysis (GO:0030162), regulation of peptidase activity (GO:0052547), regulation of cell-cell adhesion mediated by cadherin (GO:2000047), regulation of endothelial cell development (GO:1901550), positive regulation of protein kinase B signaling (GO:0051897), positive regulation of DNA biosynthetic process (GO:2000573), positive regulation of receptor internalization (GO:0002092), regulation of blood vessel endothelial cell migration (GO:0043535), positive regulation of focal adhesion assembly (GO:0051894), mononuclear cell differentiation (GO:1903131), transmembrane receptor protein tyrosine kinase signaling pathway (GO:0007169), regulation of endothelial cell proliferation (GO:0001936), positive regulation of MAPK cascade (GO:0043410), positive regulation of hydrolase activity (GO:0051345), negative regulation of RNA biosynthetic process (GO:1902679), induction of positive chemotaxis (GO:0050930), regulation of protein kinase C signaling (GO:0090036), regulation of protein modification process (GO:0031399), negative regulation of apoptotic process (GO:0043066), positive regulation of endothelial cell migration (GO:0010595), regulation of DNA-templated transcription (GO:0006355), positive regulation of phosphatidylinositol 3-kinase signaling (GO:0014068), endothelial cell migration (GO:0043542), regulation of phosphate metabolic process (GO:0019220), cellular response to decreased oxygen levels (GO:0036294), regulation of DNA biosynthetic process (GO:2000278), cell migration involved in sprouting angiogenesis (GO:0002042), cellular response to vascular endothelial growth factor stimulus (GO:0035924), positive regulation of sprouting angiogenesis (GO:1903672), positive regulation of stress-activated protein kinase signaling cascade (GO:0070304), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of transcription from RNA polymerase II promoter in response to stress (GO:0036003), regulation of endopeptidase activity (GO:0052548), regulation of protein kinase activity (GO:0045859), regulation of receptor internalization (GO:0002090), negative regulation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0043154), positive regulation of nucleic acid-templated transcription (GO:1903508), positive regulation of phosphorylation (GO:0042327), positive regulation of protein phosphorylation (GO:0001934), positive regulation of stress-activated MAPK cascade (GO:0032874), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), regulation of cell migration involved in sprouting angiogenesis (GO:0090049), positive regulation of kinase activity (GO:0033674), regulation of histone modification (GO:0031056), monocyte differentiation (GO:0030224), vascular endothelial growth factor receptor signaling pathway (GO:0048010), regulation of establishment of endothelial barrier (GO:1903140), blood vessel endothelial cell migration (GO:0043534), regulation of p38MAPK cascade (GO:1900744), vascular endothelial growth factor signaling pathway (GO:0038084), positive regulation of histone modification (GO:0031058), regulation of protein phosphorylation (GO:0001932), negative regulation of peptidase activity (GO:0010466), positive regulation of cell migration involved in sprouting angiogenesis (GO:0090050), negative regulation of DNA-templated transcription (GO:0045892), regulation of focal adhesion assembly (GO:0051893), regulation of nucleic acid-templated transcription (GO:1903506), positive regulation of MAP kinase activity (GO:0043406), regulation of protein deacetylation (GO:0090311), platelet-derived growth factor receptor signaling pathway (GO:0048008), regulation of ERK1 and ERK2 cascade (GO:0070372), regulation of phosphorylation (GO:0042325), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of protein deacetylation (GO:0090312), negative regulation of nucleic acid-templated transcription (GO:1903507), macrophage differentiation (GO:0030225), regulation of protein serine/threonine kinase activity (GO:0071900), positive regulation of peptidyl-serine phosphorylation (GO:0033138), negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of peptidyl-tyrosine phosphorylation (GO:0050731), regulation of cysteine-type endopeptidase activity (GO:2000116), positive regulation of p38MAPK cascade (GO:1900745), negative regulation of endopeptidase activity (GO:0010951), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of histone deacetylation (GO:0031063), regulation of peptidyl-tyrosine phosphorylation (GO:0050730), positive regulation of protein autophosphorylation (GO:0031954), regulation of peptidyl-serine phosphorylation (GO:0033135), regulation of protein autophosphorylation (GO:0031952), positive regulation of protein kinase activity (GO:0045860), positive regulation of histone deacetylation (GO:0031065), regulation of MAP kinase activity (GO:0043405), negative regulation of cysteine-type endopeptidase activity (GO:2000117), regulation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0043281), positive regulation of protein serine/threonine kinase activity (GO:0071902), activation of protein kinase activity (GO:0032147)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), cell surface (GO:0009986), cell junction (GO:0030054), extracellular region (GO:0005576), extracellular space (GO:0005615), cytoplasm (GO:0005737), membrane-enclosed lumen (GO:0031974), endomembrane system (GO:0012505), secretory granule (GO:0030141), cytoplasmic vesicle (GO:0031410), intracellular organelle (GO:0043229), organelle lumen (GO:0043233), anchoring junction (GO:0070161), membrane-bounded organelle (GO:0043227), cytoplasmic vesicle lumen (GO:0060205), vesicle lumen (GO:0031983), secretory vesicle (GO:0099503), intracellular membrane-bounded organelle (GO:0043231), secretory granule lumen (GO:0034774), platelet alpha granule (GO:0031091), intracellular organelle lumen (GO:0070013), vesicle (GO:0031982), cell-cell junction (GO:0005911), platelet alpha granule lumen (GO:0031093), intracellular vesicle (GO:0097708), adherens junction (GO:0005912)

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Deep Research Bioreason Rl

(VEGFA-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:55 AM

Organism: Homo sapiens

Sequence:

MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGCSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEAAVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFLLSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR

Thinking Trace

Functional Summary

UniProt Summary

Growth factor most probably involved in the regulation of angiogenesis.

InterPro Domains

Platelet-derived/Vascular endothelial growth factor (IPR050507, family) — residues 154-395
Cystine-knot cytokine (IPR029034, homologous_superfamily) — residues 215-327
PDGF/VEGF domain (IPR000072, domain) — residues 219-315
Platelet-derived growth factor, conserved site (IPR023581, conserved_site) — residues 255-267
Vascular endothelial growth factor, heparin-binding domain superfamily (IPR036841, homologous_superfamily) — residues 342-395
Vascular endothelial growth factor, heparin-binding domain (IPR027928, domain) — residues 346-395

GO Terms

Generated by BioReason

Deep Research Perplexity

(VEGFA-deep-research-perplexity.md)

provider: perplexity
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template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: VEGFA
gene_symbol: VEGFA
uniprot_accession: P15692
protein_description: 'RecName: Full=Vascular endothelial growth factor A, long form;
Short=L-VEGF {ECO:0000303|PubMed:11731620, ECO:0000303|PubMed:35455969}; AltName:
Full=Vascular permeability factor; Short=VPF; Contains: RecName: Full=N-VEGF {ECO:0000303|PubMed:35455969};
Contains: RecName: Full=VEGFA {ECO:0000303|PubMed:35455969}; Flags: Precursor;'
gene_info: Name=VEGFA; Synonyms=VEGF;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the PDGF/VEGF growth factor family.
protein_domains: Cystine-knot_cytokine. (IPR029034); PD_growth_factor_CS. (IPR023581);
PDGF/VEGF_dom. (IPR000072); PDGF/VEGF_growth_factor. (IPR050507); VEGF_C. (IPR027928)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
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return_citations: true
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citation_count: 58

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P15692
Protein Description: RecName: Full=Vascular endothelial growth factor A, long form; Short=L-VEGF {ECO:0000303|PubMed:11731620, ECO:0000303|PubMed:35455969}; AltName: Full=Vascular permeability factor; Short=VPF; Contains: RecName: Full=N-VEGF {ECO:0000303|PubMed:35455969}; Contains: RecName: Full=VEGFA {ECO:0000303|PubMed:35455969}; Flags: Precursor;
Gene Information: Name=VEGFA; Synonyms=VEGF;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the PDGF/VEGF growth factor family.
Key Domains: Cystine-knot_cytokine. (IPR029034); PD_growth_factor_CS. (IPR023581); PDGF/VEGF_dom. (IPR000072); PDGF/VEGF_growth_factor. (IPR050507); VEGF_C. (IPR027928)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "VEGFA" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'VEGFA' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene VEGFA (gene ID: VEGFA, UniProt: P15692) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Comprehensive Functional Annotation of VEGFA (Vascular Endothelial Growth Factor A)

VEGFA, located on human chromosome 6p21.1, encodes vascular endothelial growth factor A, a critical secreted signaling protein that serves as the master regulator of angiogenesis and vasculogenesis across virtually all physiological and pathological contexts.[1][3] This dimeric growth factor exists as multiple isoforms generated through alternative splicing, ranging from 121 to 206 amino acids in length, each conferring distinct bioavailability and biological potency through differential interactions with heparan sulfate proteoglycans and the extracellular matrix.[2][7][32] VEGFA functions primarily as a ligand for two receptor tyrosine kinases, VEGFR1 and VEGFR2, though it also engages the non-kinase co-receptor neuropilin-1, thereby orchestrating complex intracellular signaling cascades that promote endothelial cell proliferation, survival, migration, and increased vascular permeability.[3][4][13] The protein contains a characteristic cystine-knot motif stabilized by multiple interchain and intrachain disulfide bonds, conferring remarkable structural stability even under hypoxic conditions where oxygen availability is severely compromised.[11][19] Beyond its well-established role as a paracrine angiogenic factor, VEGFA is increasingly recognized as functioning in intracrine signaling pathways within multiple cell types including cancer cells, hematopoietic stem cells, and various macrophage populations, where nuclear-localized VEGFA and its receptors directly regulate gene expression, cell survival, and metabolic homeostasis.[48] This multifaceted protein exemplifies how alternative splicing and spatial compartmentalization of signaling create a single gene product capable of executing distinct biological functions appropriate to specific developmental, regenerative, and pathological contexts.

Gene Structure and Chromosomal Organization

The VEGFA gene spans a 16.3 kilobase coding region located at chromosome 6p21.1 on the short arm of the human genome, organized into eight exons separated by seven introns.[43] This compact genomic organization belies the remarkable diversity of VEGFA protein isoforms that can be generated from the single gene through multiple mechanisms of alternative splicing. The gene structure reflects evolutionary conservation of the PDGF/VEGF growth factor family, with sequence homology particularly evident in the regions encoding the critical cystine-knot motif and receptor-binding domains.[1] The location on chromosome 6 places VEGFA within a gene-rich region, and the genomic sequence has been characterized at high resolution through multiple reference genome assemblies including GRCh38.p14 and alternate T2T-CHM13v2.0 assemblies.[1] Beyond the constitutive elements of the gene, the regulatory landscape encompasses promoter regions responsive to multiple environmental signals including hypoxia, inflammatory cytokines, and growth factors, ensuring that VEGFA expression can be rapidly induced or suppressed in response to tissue-specific demands. The identification of multiple single nucleotide polymorphisms (SNPs) within the VEGFA locus has revealed significant associations with circulating VEGF-A levels and cardiovascular disease risk, indicating that genetic variation at this locus modulates both baseline VEGF expression and individual susceptibility to vascular disorders.[43]

Protein Structure and Cystine-Knot Motif

The VEGFA monomer adopts a distinctive three-dimensional structure anchored by a cystine-knot motif, a structural feature shared with other members of the PDGF/VEGF cytokine superfamily including platelet-derived growth factor and transforming growth factor beta.[22][31] The cystine knot consists of three disulfide bonds arranged in a topologically unique manner: the first two disulfide bridges form an eight-residue ring, through which a third disulfide bond passes, creating the characteristic knot-like topology.[22][31] Specifically, in VEGF these disulfide bonds occur between cysteines at positions 57-102, 61-104, and 26-68, with the latter passing through the ring formed by the first two.[22] This structural motif provides exceptional stability to the VEGF monomer and is essential for subsequent dimerization and receptor engagement. The VEGFA protein forms antiparallel homodimers covalently linked by two additional interchain disulfide bridges between cysteine residues 51 and 60 of each monomer, creating a molecule with approximate molecular weight of 46 kilodaltons.[22][31] Around this cystine-knot core, the VEGFA monomer contains a central four-stranded beta sheet extending from residues that form part of the receptor-binding interface.[22] The monomer structure includes an N-terminal alpha helix, which distinguishes VEGFA from PDGF and contributes to the larger buried surface area at the dimer interface compared to other cystine-knot family members.[22] This structural organization creates two symmetrical receptor-binding sites located at opposite poles of the homodimer, allowing simultaneous engagement of two VEGFR dimers and enabling the formation of higher-order signaling complexes.[22][31]

The structural stability conferred by the cystine-knot motif proves particularly important for VEGFA function under hypoxic conditions. Recent evidence demonstrates that VEGFA can efficiently complete disulfide bond formation and folding in the endoplasmic reticulum even in the absence of sufficient oxygen, unlike many other growth factors and structural proteins that become misfolded under hypoxia.[19] This oxygen-independent disulfide bond formation capability reflects selective evolutionary pressure on hypoxia-induced proteins to maintain functionality when oxygen is severely limited, suggesting that the compact disulfide architecture of VEGFA represents an adaptation for expression during the hypoxic conditions that characterize developing tissues and ischemic regions.[19] The protein contains an N-linked glycan as part of its core structure, and additional post-translational modifications including glycosylation at multiple sites throughout the molecule are essential for proper folding, secretion, and biological activity.[20] These structural features create a remarkably stable growth factor capable of maintaining signaling function across diverse physiological contexts.

Alternative Splicing and Isoform Diversity

The VEGFA gene encodes a remarkable diversity of protein isoforms through alternative splicing of exons 5, 6, 7, and 8, creating two major families of proteins with profoundly different biological properties.[2][7][57] Differential splicing of exons 6 and 7 generates the main VEGF family of proangiogenic isoforms, which exist as VEGF121, VEGF165, VEGF189, and VEGF206, corresponding to their amino acid lengths.[2][7][57] VEGF121 arises from skipping both exons 6 and 7 and represents the shortest proangiogenic form, existing as a weakly acidic polypeptide that lacks fifteen basic amino acids within the forty-four residues encoded by exon 7.[7][57] This shorter form is freely diffusible and does not bind to heparin or heparan sulfate proteoglycans, resulting in unrestricted diffusion from cells and minimal accumulation in the extracellular matrix.[7][32] In contrast, VEGF165, produced when exon 7 is retained but exon 6 is skipped, possesses a basic cluster of amino acids within its carboxyl terminus encoded by exon 7, conferring intermediate heparin-binding affinity.[7][32] This intermediate property of VEGF165 appears to represent an optimal balance between bioavailability and receptor engagement, as mice expressing only VEGF164 (the mouse ortholog) develop normally, suggesting this isoform achieves the "perfect balance" between diffusibility and heparan sulfate proteoglycan binding.[32]

The longer isoforms VEGF189 and VEGF206 retain exon 6, which encodes a twenty-four amino acid insertion highly enriched in arginine and lysine residues, creating highly basic proteins with extremely high affinity for heparin and heparan sulfate proteoglycans.[7][32] Consequently, VEGF189 and VEGF206 are predominantly sequestered in the extracellular matrix and cell surface rather than secreted into the soluble fraction, functioning as storage forms of VEGF that must be proteolytically processed by plasmin, matrix metalloproteinases, or other proteases to be released as bioactive, freely diffusible fragments.[32] This isoform-specific storage mechanism creates a spatial gradient of VEGF bioavailability, with diffusible shorter isoforms providing dynamic angiogenic signaling while matrix-bound longer isoforms serve as readily mobilizable reserves that can be activated during tissue remodeling or upon demand.[32] The differential expression of VEGF isoforms varies by tissue type and developmental stage, with longer isoforms predominating in certain tissues such as normal lung tissue, while shorter isoforms become relatively enriched in cancer and during pathological angiogenesis.[57]

Beyond the primary family of proangiogenic isoforms, alternative splice-site selection within exon 8 generates an entirely different class of proteins termed VEGF165b, VEGF121b, and related antiangiogenic variants.[2][7][38] Alternative splicing at the 3' end of exon 8 produces two mutually exclusive exon sequences: exon 8a encoding cysteine-aspartate-lysine-proline-arginine-arginine and exon 8b encoding serine-leucine-threonine-arginine-lysine-aspartate.[7] These six C-terminal amino acid differences confer radically different functional properties, with VEGF165b and other VEGFxxxb isoforms demonstrating antiangiogenic activity that opposes the proangiogenic effects of their conventional VEGF165 and VEGFxxx counterparts.[2][38] The antiangiogenic isoforms are expressed at elevated levels in normal, quiescent tissues but become dramatically downregulated in angiogenic diseases including cancer, proliferative retinopathy, and developmental pathologies such as preeclampsia and Denys-Drash syndrome.[2][38] These observations suggest that the balance between pro- and antiangiogenic VEGF isoforms may represent a fundamental regulatory mechanism controlling angiogenic potential, with loss of antiangiogenic isoforms contributing to pathological angiogenesis in disease states.

VEGF Receptor Structure and Binding Interactions

VEGFA exerts its biological effects primarily through two receptor tyrosine kinases designated VEGFR1 (also known as Flt-1 or FMS-like tyrosine kinase 1) and VEGFR2 (also known as KDR or kinase domain region), though it also engages co-receptors including neuropilin-1 and neuropilin-2.[3][6][13] Both VEGFR1 and VEGFR2 are membrane-bound receptor tyrosine kinases belonging to the split kinase domain family of receptors, featuring seven immunoglobulin-like extracellular domains, a single transmembrane spanning region, and an intracellular domain containing a split tyrosine kinase.[6][13][14] The extracellular portions of both receptors, particularly the immunoglobulin-like domains 2 and 3 (IgD2 and IgD3), provide the primary VEGF-binding surfaces.[14][17] Despite structural similarity, VEGFR1 and VEGFR2 differ substantially in their functional consequences when activated by VEGF: VEGFR1 binds VEGF-A with approximately 50-fold higher affinity than VEGFR2, yet exhibits only weak tyrosine phosphorylation in endothelial cells upon VEGF-induced dimerization, resulting in minimal activation of downstream angiogenic signaling.[6][30] In contrast, VEGFR2 demonstrates more robust tyrosine phosphorylation upon VEGF engagement and mediates essentially all of the characterized pro-angiogenic responses to VEGF in endothelial cells, including proliferation, survival, migration, and vascular permeability.[3][6][13][14]

This apparent paradox of higher binding affinity paired with weaker signaling at VEGFR1 is resolved through understanding the distinct biological roles of these receptors: VEGFR1 functions primarily as a negative regulator of VEGFR2 signaling during early vascular development, and can function as a decoy receptor sequestering VEGF from VEGFR2 engagement.[6][30] A soluble splice variant of VEGFR1 designated sFlt-1 (soluble fms-like tyrosine kinase 1) is secreted and functions as a circulating VEGF trap, effectively neutralizing circulating VEGF and preventing its interaction with cell surface VEGFR2.[6][30] This regulatory mechanism becomes physiologically critical during pregnancy, where the balance between circulating VEGF-A and sFlt-1 determines vascular permeability and endothelial function; dysregulation of this balance contributes to preeclampsia pathogenesis.[6] A third VEGF receptor designated VEGFR3 mediates responses to VEGF-C and VEGF-D but does not serve as a VEGF-A ligand, instead functioning in lymphangiogenesis.[6]

The co-receptor neuropilin-1 dramatically enhances VEGF signaling through mechanisms that remained incompletely understood until recent research clarified its role. VEGF165, the predominant isoform, binds to neuropilin-1 through its heparin-binding domain encoded by exon 7, whereas the shorter VEGF121 isoform, lacking exon 7, does not bind neuropilin-1.[8][9][12] The crystal structure of neuropilin-1 b1b2 domains in complex with a VEGF-derived peptide revealed that the basic tail of VEGF165 interacts directly with acidic residues on the neuropilin-1 b1 domain, with heparin serving as a critical bridge molecule that enhances the interaction between VEGF, neuropilin-1, and the extracellular matrix.[8][9] Surprisingly, recent genetic evidence demonstrates that neuropilin-1 promotes angiogenesis not primarily through enhancing VEGF binding, but rather through functioning as a co-receptor that regulates cell surface expression and trafficking of VEGFR2.[12] Specifically, neuropilin-1 guides internalized VEGFR2 from lysosomal degradation pathways into Rab11-positive recycling vesicles, thereby stabilizing VEGFR2 at the cell surface and amplifying VEGFR2-VEGF signaling.[12] This co-receptor function explains how neuropilin-1 can regulate angiogenesis even when direct VEGF-neuropilin-1 binding is disrupted, establishing neuropilin-1 as a critical regulator of endothelial cell responsiveness to VEGF rather than solely a ligand-binding protein.

VEGFR2 Signaling Pathways and Downstream Effectors

Upon VEGF-A binding and VEGFR2 dimerization, the receptor undergoes rapid autophosphorylation at multiple tyrosine residues within its intracellular domains, with each phosphorylation site serving as a docking platform for specific signaling adaptor proteins that initiate distinct downstream cascades.[14][17] The juxtamembrane domain tyrosine Y801 undergoes phosphorylation as part of the activation mechanism, where in its unphosphorylated state this domain physically interacts with the kinase domain activation loop in an autoinhibitory configuration.[14] Phosphorylation at Y801 relieves this autoinhibition, allowing the kinase domain to adopt an active conformation capable of transphosphorylating additional tyrosine residues.[14] Within the kinase domain proper, phosphorylation at Y951 and Y1054/Y1059 further enhance kinase catalytic activity, while the C-terminal domain contains critical sites at Y1175 and Y1214 that recruit specific effector proteins.[14][17]

The phosphorylated Y1175 residue recruits phospholipase C-gamma (PLCγ) through its SH2 domain, initiating the PLCγ-PKC-MAPK pathway that represents the predominant pro-proliferative signal in endothelial cells.[13][14][17][25] PLCγ activation catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), leading to activation of protein kinase C (PKC) and elevation of intracellular calcium concentration.[13][17] PKC then activates the Raf-MEK-ERK mitogen-activated protein kinase cascade, which translocates into the nucleus and activates transcription factors that induce gene expression required for endothelial cell DNA synthesis and proliferation.[13][17] Notably, analysis of VEGF-A isoforms reveals that different isoforms differentially activate this critical Y1175-PLCγ pathway, with VEGF165 inducing much greater ERK1/2 phosphorylation than VEGF121, suggesting that isoform-specific differences in signaling capacity may explain their distinct biological potencies.[2] The differential coupling to this pathway operates through variations in receptor phosphorylation kinetics, with VEGF165 stimulation of endothelial cells producing greater and more sustained VEGFR2 Y1175 phosphorylation compared to VEGF121.[2]

Phosphorylation of VEGFR2 at Y951 within the kinase insert domain initiates the TSAd-Src-PI3K-Akt pathway, which is essential for endothelial cell survival.[13][14][17] Src-family kinases are recruited to phosphorylated Y951 and subsequently activate phosphoinositide 3-kinase (PI3K), which catalyzes the conversion of PIP2 to phosphatidylinositol 3,4,5-trisphosphate (PIP3).[14][17] PIP3 then recruits and activates protein kinase B (Akt/PKB), which phosphorylates and thereby inactivates pro-apoptotic proteins including BAD (BCL2-associated agonist of cell death) and caspase-9, ensuring endothelial cell survival under VEGF stimulation.[14][17] This survival signal proves critical for maintaining vascular integrity and preventing endothelial cell loss under stress conditions. Additionally, Y951-mediated PI3K-Akt activation contributes to vascular permeability through parallel mechanisms including Rac1 GTPase activation and reactive oxygen species production.[33]

Phosphorylation at Y1214 recruits the NCK adaptor protein and initiates signaling through p38 MAPK and downstream MAPKAPK2/3 kinases, leading to actin remodeling and endothelial cell migration essential for angiogenic sprouting.[14][17][51] This pathway also involves activation of small GTPases including Rac and Cdc42, which orchestrate cytoskeletal reorganization required for directed cell movement.[14][51] The Y1175 site also recruits SHB adaptor protein, linking to FAK (focal adhesion kinase) and paxillin through a separate signaling axis that modulates focal adhesion turnover and cellular motility.[14] Collectively, these multiple phosphorylation sites on VEGFR2 enable the single VEGF ligand to activate multiple distinct signaling pathways within a single cell, allowing VEGF to simultaneously promote proliferation, survival, and migration—the three key endothelial functions required for effective angiogenesis.

Recent evidence has identified an additional layer of complexity in VEGFR2 signaling through the discovery that integrin αvβ3 can directly bind the heparin-binding domain of VEGF165, and that this integrin-VEGF interaction regulates VEGFR2 signaling.[35] Specifically, binding sites for integrin αvβ3 and VEGFR2 domain 1 overlap within the heparin-binding domain of VEGF165, suggesting that these two receptors compete for VEGF binding at this site.[35] The functional consequence of αvβ3 binding to VEGF165 is suppression of KDR domain 1 binding and reduced ERK1/2 and Akt phosphorylation, indicating that integrin αvβ3 can function as a negative regulator of VEGF signaling through competitive receptor binding.[35]

Biological Functions in Angiogenesis and Vasculogenesis

VEGF-A functions as the master regulator of angiogenesis, the process of new blood vessel formation from pre-existing vasculature, and vasculogenesis, the de novo formation of blood vessels from vascular progenitor cells, across all developmental and adult contexts.[52] During embryonic development, VEGF is initially expressed at high levels in the yolk sac and at embryonic sites of vessel formation, supporting the assembly of the cardiovascular system beginning around embryonic day 7.5 to 8.0 in mice.[49][52] The spatial localization of VEGF expression in the anterior mesoderm and its co-localization with VEGFR-expressing cells in posterior regions establishes a chemotactic gradient guiding vascular progenitor cell migration from posterior developmental regions toward anterior embryonic structures including the developing heart and forebrain.[49] This gradient-dependent cell migration represents a critical early step in cardiovascular morphogenesis, as inhibition of VEGFR signaling during this window substantially impairs the accumulation and migration of VEGFR-positive cells to their destination tissues.[49]

The process of vasculogenic tubulogenesis—the transformation of solid aggregates of endothelial progenitors (angioblasts) into patent blood vessels—depends absolutely on VEGFR2 signaling, as demonstrated by the embryonic lethality of VEGFR2 null mice at approximately embryonic day 8.5.[52] The development of a functional vascular network proceeds through distinct stages, beginning with the formation of primitive vascular plexuses that subsequently undergo sprouting angiogenesis and vascular remodeling to establish a hierarchical organization of vessels of varying diameters and functions.[44] VEGF initiates sprouting angiogenesis through multiple mechanisms: it stimulates endothelial cell proliferation through the PLCγ-PKC-MAPK pathway, promotes directed migration of endothelial cells through Rac1 and Cdc42-mediated actin remodeling, and increases vascular permeability to facilitate plasma protein extravasation and infiltration of supporting cells.[3][4][51] The temporal progression of VEGF expression during wound healing illustrates this multifaceted role: VEGF levels are dramatically upregulated 3-7 days post-wounding, the proliferative phase of repair during which capillary growth and differentiation peak, and VEGF neutralization with blocking antibodies substantially diminishes both chemotactic and angiogenic properties of wound fluid.[58]

The formation of vascular lumens, the hollow centers through which blood flows, involves specialized VEGF-mediated signaling and endothelial cell polarization mechanisms. During lumen formation, VEGF-activated endothelial cells must undergo dramatic morphological changes including actin remodeling, vesicle-mediated trafficking to the luminal membrane, and junctional reorganization to establish the inside versus outside orientation of developing vessels.[44] This process appears to involve multiple mechanisms coordinating simultaneously: Rab7-directed vectorial transport of vesicles to expand the developing lumen at the cord center, and concurrent redistribution of junctional proteins away from the cord center to preserve peripheral cell-cell contacts while creating a hollow channel.[44] The importance of endothelial cell polarity is evidenced by studies showing that loss of β1 integrin, which disrupts Par3 localization and endothelial polarity, results in accumulation of cytosolic Rab7+ vesicles and failure of vascular lumen formation despite apparently normal early vasculogenesis.[44]

VEGF Secretion, Trafficking, and Subcellular Localization

VEGF-A contains an N-terminal signal sequence targeting it to the lumen of the endoplasmic reticulum, where the nascent protein undergoes rapid dimerization through disulfide bond formation and co-translational oxidation.[20] The trafficking of VEGF from the endoplasmic reticulum through the secretory pathway to the cell surface requires specific small GTPases: Sar1 and Arf1 regulate VEGF165 movement between the endoplasmic reticulum and Golgi apparatus, while post-Golgi transport depends critically on N-linked glycosylation, a modification occurring within the Golgi compartment.[20] These early secretory steps can be regulated by signaling pathways; phorbol ester-induced protein kinase C activation, for instance, promotes VEGF165 secretion by increasing the flux through the entire secretory pathway, while the effect appears sensitive to intracellular calcium elevation.[20] A striking feature of VEGF165 trafficking is that a substantial fraction of the protein localizes to the outer surface of the plasma membrane in a punctate, string-like pattern rather than being immediately secreted into the surrounding medium.[20] From this plasma membrane location, approximately 50% of VEGF165-GFP undergoes shedding from the cell surface in association with membrane vesicles and other membrane components, suggesting a mechanism for regulated release of VEGF into the immediate microenvironment.[20]

Beneath the well-characterized extracellular functions of VEGF lies an emerging role for intracellular VEGF signaling termed intracrine signaling, wherein VEGF functions as a signaling molecule within cells without prior secretion.[48] Nuclear-localized VEGF and VEGFR2 have been detected in multiple cell types including endothelial cells, cancer cells, and hematopoietic cells, and evidence suggests these intracellular receptors participate in direct regulation of nuclear gene expression and metabolic homeostasis.[48] In cultured endothelial cells, VEGF knockdown results not in classical markers of apoptosis such as cleaved caspase-3, but rather in dramatic mitochondrial fragmentation accompanied by reduced metabolic activity and depressed mitochondrial function, suggesting intracrine VEGF maintains normal cellular metabolism through mitochondrial regulation.[48] In cancer cells including acute myeloid leukemia cells, a pool of VEGFR1 localizes to the nucleus rather than the cell surface, and neutralizing anti-VEGF antibodies reduce nuclear VEGFR2 localization while shifting it toward the cell surface, indicating that autocrine VEGF released within cells promotes nuclear localization of its receptors.[48] The specific mechanisms by which nuclear-localized VEGF and VEGFR regulate transcription remain to be fully elucidated, but evidence suggests non-kinase functions of intracellular VEGFR1 may be involved, as some effects cannot be blocked by tyrosine kinase inhibitors.[48] These intracrine functions expand the biological scope of VEGF beyond its classical role as a paracrine angiogenic factor, establishing it as a regulator of fundamental cellular processes including energy metabolism and survival.

Regulation of VEGF Expression

VEGF-A gene expression is regulated by multiple transcriptional and post-transcriptional mechanisms responsive to physiological and pathological signals. Hypoxia represents perhaps the most important physiological regulator of VEGF expression, acting through the hypoxia-inducible factor-1 (HIF-1) pathway wherein low oxygen tension stabilizes HIF-1α protein, which heterodimerizes with HIF-1β and directly binds to hypoxia response elements in the VEGFA promoter region.[21] However, VEGF regulation in certain contexts proceeds through HIF-1-independent pathways, as evidenced by studies showing that in hepatocellular carcinoma cells, VEGF expression remains substantially elevated even when HIF-1α is genetically suppressed, with this HIF-1-independent expression controlled by phosphoinositide 3-kinase and transcription factor SP1.[21] This pathway diversity ensures that VEGF can be rapidly mobilized under conditions of metabolic stress regardless of the specific mechanism triggering cellular adaptation.

Genetic variation at the VEGFA locus, particularly single nucleotide polymorphisms in the gene sequence or regulatory regions, influences baseline VEGF-A levels and individual susceptibility to cardiovascular disease and other vascular disorders.[43] Multiple VEGFA SNPs including rs6921438, rs4416670, rs6993770, and rs10738760 distributed across three chromosomes have been associated with circulating VEGF-A levels, collectively explaining up to 52% of the variance in total circulating VEGF-A.[43] The rs2010963 SNP in exon 1 of VEGFA associates with differential cardiovascular outcomes in different populations, with the CC/GC genotypes conferring increased risk of cardiac death within a five-year follow-up period in some coronary artery disease cohorts.[43] These genetic associations underscore how VEGF-A levels and signaling capacity are subject to substantial individual genetic variation, potentially explaining differential responsiveness to anti-VEGF therapeutics and variable disease progression among individuals exposed to similar risk factors.

At the post-transcriptional level, VEGF-A mRNA undergoes polyadenylation and export from the nucleus, and stability of VEGF mRNA is modulated by microRNA interactions and RNA-binding proteins.[21] The VEGF gene also contains a precursor form arising from initiation at an upstream in-frame CUG codon rather than the standard AUG initiation codon, generating a 47 kilodalton VEGF165 precursor with a 180-residue N-terminal extension.[15] This precursor form is processed by proteolytic cleavage and appears to have different properties than mature VEGF, as the precursor does not induce endothelial cell proliferation or expression of angiopoietin-2, yet adheres to the extracellular matrix, suggesting potential roles as a storage form or for localized VEGF generation.[15]

VEGF in Wound Healing and Tissue Regeneration

VEGF-A emerges as a uniquely important growth factor for ischemic wound healing, a conclusion supported by comparative studies demonstrating that VEGF surpasses basic fibroblast growth factor in promoting healing when tissue ischemia is the primary pathological driver.[55] During normal wound healing, VEGF mRNA expression is induced 3-5 fold by ischemia alone and 6-7 fold by wounding, with this upregulation evident as early as one day following injury and persisting throughout the experimental observation period.[55] The effect of exogenous VEGF165 application to wounds demonstrates substantially greater efficacy than VEGF121 in promoting granulation tissue formation: in nonischemic wounds, VEGF121 and VEGF165 application increased granulation tissue by 50% and 70% respectively at day 10, while ischemic wounds showed even more dramatic effects with VEGF165 producing the larger responses.[55] Mechanistically, VEGF promotes wound healing through multiple complementary pathways: it serves as an endothelial cell mitogen driving angiogenesis that improves tissue oxygenation, acts as a chemoattractant for endothelial cells and inflammatory cells including macrophages, increases vascular permeability to enhance delivery of plasma proteins and cellular infiltration into the wound site, and induces endothelial cells to secrete numerous bioactive growth factors and cytokines that support fibroblast function and tissue remodeling.[55][58] Notably, while VEGF powerfully promotes granulation tissue formation and angiogenesis, it has minimal effect on new epithelium formation, suggesting distinct mechanisms drive different components of the wound healing cascade.[55] This angiogenesis-focused role makes physiological sense, as VEGF acts primarily on endothelial cells, whereas epithelial cell growth requires other factors including keratinocyte growth factor, which fibroblasts produce in response to other signals.[55]

During skeletal muscle regeneration following injury, VEGF-A emerges as a critical mediator of the intercellular communication networks coordinating diverse cell types including myogenic progenitors, stromal fibroblasts, hematopoietic cells, and endothelial cells.[45] Remarkably, the source of VEGF-A production determines its function despite the ligand being identical: VEGF-A produced by myogenic progenitors and stromal fibroblasts exerts distinct effects on endothelial cell engagement and the trajectory of regeneration.[45] This spatial compartmentalization of signaling illustrates a fundamental principle wherein the same secreted factor executing identical molecular interactions can achieve distinct biological outcomes based on its cellular source and microenvironmental context. This observation suggests that anti-VEGF therapeutics targeting the total circulating VEGF may inadvertently eliminate tissue-autonomous VEGF functions that are incompletely captured by studies of circulating VEGF levels alone.

Pathological VEGF Signaling in Cancer

Tumor angiogenesis represents perhaps the most clinically important pathological consequence of VEGF dysregulation, as developing tumors require new blood vessel formation to grow beyond a size of 1-2 millimeters.[37] VEGF is dramatically upregulated in the vast majority of solid tumors and hematologic malignancies, with VEGF levels correlating with aggressive disease progression and increased metastatic potential.[37] The autocrine production of VEGF by tumor cells themselves, in addition to paracrine VEGF production by stromal cells, creates a microenvironment heavily biased toward angiogenesis, with increased vascular density supporting nutrient delivery and facilitating metastatic dissemination.[37] Beyond promoting angiogenesis via endothelial cells, evidence increasingly indicates that VEGF directly supports tumor cell survival and proliferation through autocrine signaling, as reduced VEGF expression in multiple cancer cell lines induces apoptosis and dramatically reduces cell proliferation and invasiveness.[39] In renal clear cell carcinoma, genetic suppression of VEGFA via RNA interference dramatically decreases phosphorylated-AKT and phosphoinositide 3-kinase expression, substantially inhibits cell proliferation, markedly increases apoptotic rates, and suppresses cell migration and invasion capacity, indicating that the PI3K/AKT pathway mediates tumor cell autonomous effects of VEGF.[39]

The pro-angiogenic effect of VEGF165 versus the antiangiogenic effect of VEGF165b isoforms illuminates potential therapeutic opportunities through manipulation of VEGF isoform balance rather than simply blocking all VEGF signaling.[38] Tumors expressing high levels of VEGF165 grow rapidly in murine xenograft models, while tumors engineered to express VEGF165b show substantially reduced growth associated with diminished microvascular density.[38] When VEGF165b and VEGF165 are co-expressed in tumors, the growth rate is intermediate between the two single-isoform expressing tumors, suggesting that VEGF165b actively antagonizes the angiogenic effects of VEGF165.[38] The mechanism by which VEGF165b exerts its antiangiogenic activity involves binding to both VEGFR1 and VEGFR2, but initiating only weak signaling through these receptors that is insufficient to promote endothelial cell proliferation or migration.[38] This weak agonist activity allows VEGF165b to compete with VEGF165 for receptor occupancy while not providing sufficient signaling to drive angiogenesis, thereby functioning as a competitive inhibitor of pro-angiogenic VEGF signaling.[38]

Beyond its classical pro-angiogenic role, VEGF-A signaling directly affects tumor cell biological behavior through multiple mechanisms. In epithelial ovarian cancer, an activated tumor cell VEGFR2/AKT/mTOR pathway associates with increased ascites incidence and reduced overall survival in cisplatin-taxane treated patients with serous histology, suggesting that VEGF signaling acts on tumor cells as a direct stimulator of the AKT/mTOR protein synthesis pathway rather than acting solely through endothelial cells.[42] This finding implies that anti-VEGF therapeutics exert anti-tumor effects through at least two distinct mechanisms: direct suppression of tumor cell growth signaling and indirect effects through inhibition of tumor angiogenesis.[42] The existence of direct VEGF-VEGFR signaling in tumor cells raises important mechanistic questions regarding the design and targeting of anti-VEGF therapeutics, suggesting that approaches enabling discrimination between endothelial and tumor cell VEGF signaling could improve therapeutic specificity.

VEGF in Regulation of Vascular Permeability and Leukocyte Infiltration

VEGF-A functions as a potent regulator of vascular permeability, a property reflected in its alternative name as vascular permeability factor (VPF), and serves as a critical mediator of vascular barrier dysfunction in both physiological and pathological contexts.[3][33][36] The mechanism by which VEGF increases vascular permeability involves multiple signaling pathways: direct phosphorylation of endothelial junctional proteins including occludin and zonula occludens-1 (ZO-1), downregulation of occludin and claudin expression, production of reactive oxygen species through Rac1-mediated mechanisms, and activation of Rho GTPases leading to cytoskeletal contraction and junctional disruption.[33] VEGF-induced Rac1 activation requires VEGFR2, active Src tyrosine kinase, the guanine nucleotide exchange factor Vav2, and ultimately Rac1 itself, establishing a signaling cascade from plasma membrane receptor engagement to GTPase activation driving actin reorganization.[33] Recent evidence indicates that VEGF also regulates vascular permeability through modulation of tight junction protein phosphatase activity: reactive oxygen species produced downstream of Rac activation can inactivate protein phosphatases by oxidizing critical cysteine residues in their catalytic sites, thereby preventing dephosphorylation of occludin and ZO-1 and maintaining their phosphorylated, permeability-increasing state.[33]

The regulation of endothelial junctional integrity by VEGF has been connected to macrophage functions through the discovery that the junctional adhesion molecule JAM-A positively regulates endothelial tight junction integrity by suppressing VEGF-A and VEGFR2 levels through downregulation of HIF-1α and transcription factor Id1.[36] JAM-A knockout mice demonstrate significantly enhanced basal vascular permeability compared to wild-type controls, with this enhanced permeability associated with a three-fold increase in plasma VEGF-A and significantly increased VEGFR2 mRNA and protein levels in endothelial cells.[36] Critically, inhibition of VEGFR2 using function-blocking antibodies completely abrogates both basal and VEGF-induced vascular permeability in JAM-A knockout mice, demonstrating that the enhanced permeability phenotype results from enhanced VEGF/VEGFR2 signaling rather than from structural defects in tight junctions.[36] This molecular mechanism reveals how loss of junctional protein expression can indirectly increase VEGF/VEGFR2 signaling through de-repression of VEGF transcription factors, creating a feedback loop wherein junctional dysfunction amplifies angiogenic signaling.

VEGF-A also regulates leukocyte-endothelial interactions through modulation of endothelial adhesion molecule expression. VEGF-A isoforms differentially regulate expression of vascular cell adhesion molecule-1 (VCAM-1), a key mediator of endothelial-leukocyte interactions, through isoform-specific stimulation of ERK1/2 and activating transcription factor-2 (ATF-2) phosphorylation.[2] The VEGF-A165 isoform induces significantly greater VCAM-1 expression than VEGF-A121, resulting in increased leukocyte recruitment to VEGF-stimulated endothelium.[2] This differential regulation operates through isoform-specific kinetics of VEGFR2 phosphorylation and downstream signaling, with ATF-2 functioning as a nuclear "switch" converting short-term cytosolic-to-nuclear signaling into long-term endothelial responses including leukocyte recruitment.[2] The discovery of this switch mechanism illustrates how distinct VEGF-A isoforms with similar receptor-binding affinities can program differential endothelial responses through variations in signaling kinetics and substrate specificity.

VEGF Signaling in Immune Cell Modulation

Beyond its classical functions in endothelial cells, VEGF-A exerts important regulatory functions in immune cell biology, particularly in macrophage phenotypic differentiation and function. IL-4, a prototypical macrophage-polarizing cytokine, coordinately regulates the VEGFA-VEGFR1 (FLT1) axis in alternatively polarized macrophages by simultaneously inhibiting pro-angiogenic VEGFA expression and inducing antiangiogenic soluble FLT1 expression through IL-4-STAT6 signaling and EGR2 transcription factor induction.[56] This IL-4-mediated shift in the VEGFA/sFLT1 balance transforms alternatively polarized macrophages into cells with attenuated pro-angiogenic capacity, suggesting that macrophage polarization state directly determines their contribution to angiogenesis regulation.[56] Furthermore, VEGF treatment of M1 pro-inflammatory macrophages suppresses M1 markers including CXCL10, IL-12, and CCR7, while simultaneously upregulating M2 markers including CD206 and CD163, demonstrating that VEGF can directly promote macrophage polarization toward an alternatively activated M2 phenotype.[59] This pro-M2 effect of VEGF provides a potential mechanism whereby VEGF-rich tumoral microenvironments promote infiltration of M2 macrophages that support tumor growth and suppress anti-tumor immunity.[59]

VEGF also functions as a chemoattractant for monocytes and macrophages, promoting their infiltration into tissues under conditions of hypoxia and inflammation.[59] The underlying molecular mechanism involves VEGF engagement of VEGFR1 on monocyte/macrophage surfaces, with evidence suggesting that both VEGFR1 and VEGFR2 are expressed on these cells with VEGFR1 demonstrating particularly high expression in M1 macrophages.[59] This pro-migratory effect has been documented in multiple model systems, including during uterine decidualization where conditioned medium from VEGF-producing decidualized endometrial stromal cells promotes macrophage migration in a manner dependent on VEGF, as blockade with soluble FLT1 substantially reduces macrophage recruitment.[59] In hematopoietic stem cells, evidence suggests that VEGF functions through intracrine signaling involving VEGFR1 to promote stem cell survival and in vivo repopulation capacity, suggesting intracellular VEGF-VEGFR1 signaling plays roles beyond endothelial regulation.[48]

VEGF in Developmental Organogenesis

Beyond cardiovascular development, VEGF-A functions as an instructive signal for development of multiple organ systems, with experiments employing VEGF isoform-specific transgenic mice revealing that the balance of VEGF isoforms critically determines proper organ patterning and function. Mice expressing only VEGF120 (the mouse ortholog of human VEGF121) develop normally through birth, establishing that VEGF120 alone suffices to support vasculogenesis and overall VEGF functions.[52] However, these VEGF120/120 mice display defects in multiple organ systems including the heart, retina, bone, kidney, and lung, indicating that longer VEGF isoforms provide essential contributions to organ-specific vascular development and function.[52] Conversely, mice expressing only VEGF188 (the mouse ortholog of human VEGF189) suffer approximately 50% prenatal lethality due to severe defects in aortic arch remodeling, and surviving animals show defects in artery development in the eye and impaired epiphyseal bone vascularization.[52] These isoform-specific phenotypes indicate that the relative balance of diffusible versus matrix-bound VEGF isoforms—not merely the absolute level of total VEGF—determines proper vascular patterning during development and organ formation.[52]

In bone development, the spatial and temporal expression of VEGF isoforms is mechanically controlled by tissue tension, with VEGF189 preferentially expressed under conditions of increased stretch-induced cellular tension where it plays a role in vascularization during bone repair and remodeling.[52] This mechanical regulation of VEGF isoform expression exemplifies how developmental and tissue remodeling processes employ VEGF signaling with exquisite spatial and temporal specificity to achieve proper morphogenesis. The retention of longer VEGF isoforms in the extracellular matrix under mechanical stress conditions may create local reservoirs that can be mobilized during subsequent bone remodeling or fracture repair, providing a mechanism for coupling mechanical signals to angiogenic responses.

Conclusion

VEGFA represents a paradigm of molecular multivalency wherein alternative splicing of a single gene generates distinct protein isoforms with profoundly different biological properties, spatial localization, and receptor engagement profiles, enabling execution of context-appropriate functions across development, tissue homeostasis, regeneration, and disease.[2][7][57] The cystine-knot structure of VEGFA confers remarkable stability and compact architecture permitting efficient disulfide bond formation even under the hypoxic conditions characteristic of developing tissues and ischemic disease states, enabling rapid mobilization of angiogenic signaling when oxygen availability becomes limiting.[11][19] The complexity of VEGF signaling extends far beyond canonical ligand-receptor binding at the cell surface, encompassing intracrine mechanisms wherein nuclear-localized VEGF and its receptors directly regulate gene expression and metabolic homeostasis within multiple cell types, expanding the biological scope of this molecule beyond classical paracrine angiogenic signaling.[48]

The discovery that the cellular source of VEGF-A determines its biological function despite molecular identity, and that spatial compartmentalization of signaling creates functionally distinct VEGF-mediated responses in myogenic progenitors versus stromal fibroblasts, reveals fundamental principles of intercellular communication wherein identical secreted factors execute distinct functions based on microenvironmental context.[45] The differential ability of VEGF165 and VEGF165b isoforms to activate or antagonize angiogenesis while possessing identical receptor-binding domains suggests that post-translational modifications or conformational mechanisms enable these isoforms to achieve opposite biological outcomes, highlighting mechanistic complexity that remains incompletely understood.[2][38] The regulation of VEGF expression and isoform balance through HIF-1-dependent and HIF-1-independent pathways ensures that VEGF mobilization occurs rapidly in response to metabolic stress through redundant mechanisms, while the modulation of VEGF action by receptor co-factors including neuropilin-1 adds additional layers of signal amplification and specificity.[12][21]

Future investigations of VEGFA biology will likely focus on elucidating the mechanisms by which VEGF isoform-specific differences in C-terminal sequences achieve differential receptor signaling kinetics and specificity, clarifying the functional significance and mechanisms of intracrine VEGF signaling in cancer and stem cell biology, and determining how spatial compartmentalization of VEGF production by distinct cell types within complex tissues translates molecular signals into distinct biological outcomes. The therapeutic targeting of VEGFA has emerged as a major treatment modality for multiple cancers through monoclonal antibodies and small-molecule receptor inhibitors, yet substantial therapeutic resistance develops in many cases, suggesting that understanding redundant VEGF pathways, cell-autonomous VEGF effects on tumor cells, and potentially isoform-specific contributions to tumor pathogenesis may enable development of next-generation therapeutics with improved efficacy.[37][42] The balance between pro-angiogenic VEGF isoforms and antiangiogenic VEGF-b variants in controlling physiological versus pathological angiogenesis offers potential therapeutic opportunities through isoform-selective modulation rather than global VEGF inhibition, a strategy that might preserve beneficial angiogenesis in wound healing and ischemic disease while suppressing pathological tumor angiogenesis.

Citations

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Notes

(VEGFA-notes.md)

VEGFA Notes - ISOFORMS Project

Key Isoform Biology

VEGFA has 17 named isoforms from alternative splicing, representing extreme diversity in isoform function.

Major Isoforms by Length

Isoform	UniProt ID	Length	Heparin Binding	Matrix Bound	Key Feature
VEGF206	P15692-1	206 AA	Strong	Yes	Longest, matrix-bound
VEGF189	P15692-2	189 AA	Strong	Yes	Matrix-bound
VEGF165	P15692-4	165 AA	Moderate	Intermediate	Canonical "VEGF"
VEGF121	P15692-9	121 AA	None	No	Freely diffusible
VEGF165B	P15692-8	165 AA	?	?	ANTI-ANGIOGENIC

Critical Isoform Difference: VEGF165 vs VEGF165B

UniProt explicitly states for VEGF165B:

"Binds to the KDR receptor but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth" PMID:15520188

This means:
- VEGF165: Pro-angiogenic, promotes tumor growth
- VEGF165B: Anti-angiogenic, inhibits tumor growth

Same length (165 AA), same receptor binding, but opposite biological effects!

Heparin Binding and Matrix Association

The longer isoforms (VEGF189, VEGF206) contain heparin-binding domains and remain matrix-bound, creating:
- Steep gradients - important for vessel sprouting
- Localized signaling - concentrated at source

The shorter isoform (VEGF121) lacks heparin binding:
- Freely diffusible - spreads through tissue
- Broad signaling - less directional

GOA Annotation Status

267 total annotations
NO isoform-specific annotations (no P15692-X identifiers)
Likely conflates pro-angiogenic (most isoforms) with anti-angiogenic (VEGF165B) functions

Expected Annotation Issues

Angiogenesis annotations - should specify which isoforms
"Positive regulation of angiogenesis" - NOT true for VEGF165B
VEGFR binding - all isoforms bind, but different downstream effects

Key References

PMID:15520188 - VEGF165B anti-angiogenic properties
Original VEGF papers describing isoform differences

Bioreason Rl Review

(VEGFA-bioreason-rl-review.md)

BioReason-Pro RL Review: VEGFA (human)

Source: VEGFA-deep-research-bioreason-rl.md

Correctness: 5/5
Completeness: 3/5

Functional Summary Review

The BioReason functional summary states:

A secreted human growth factor that adopts a cystine-knot architecture to signal as a high-affinity ligand for endothelial receptor tyrosine kinases. By forming a disulfide-stabilized dimer and using a C-terminal glycosaminoglycan-binding tail, it concentrates at the extracellular matrix and basement membranes, where it potently drives endothelial signaling pathways that promote blood vessel formation and remodeling.

This is an accurate summary that correctly captures VEGFA's core identity. The curated review describes VEGFA as "the master regulator of angiogenesis." BioReason correctly identifies:

The cystine-knot cytokine fold and PDGF/VEGF domain
Disulfide-stabilized dimerization
Heparin-binding domain for matrix retention
Growth factor activity (GO:0008083)
Endothelial receptor tyrosine kinase signaling
Angiogenesis (GO:0001525)
Extracellular localization

However, there are significant completeness gaps:

Isoform biology omitted: The curated review emphasizes that VEGFA's "CRITICAL ISOFORM BIOLOGY" with 17 splice variants is central to understanding its function. VEGF121 is freely diffusible, VEGF165 is the predominant isoform, and VEGF165b is anti-angiogenic. BioReason treats the protein as a single entity.
Receptor specificity absent: VEGFR1 (FLT1) and VEGFR2 (KDR) are not mentioned. VEGFR2 mediates most angiogenic signaling while VEGFR1 acts as a decoy receptor.
Anti-angiogenic isoforms: The existence of VEGF-xxxb isoforms that bind VEGFR2 but fail to activate signaling is a key finding not captured.
Vascular permeability: VEGFA was originally identified as "vascular permeability factor" -- this function is not mentioned.
Non-endothelial functions: Neuroprotective effects, immune cell regulation, and bone development roles are absent.

Comparison with interpro2go:

The interpro2go annotations from IPR000072 (PDGF/VEGF domain) and IPR050507 (PDGF/VEGF family) would map to growth factor activity and receptor binding. BioReason reproduces these and adds useful context about the heparin-binding domain's role in matrix concentration and the cystine-knot dimerization mechanism. The predicted GO terms include VEGF receptor binding (GO:0005172) and growth factor activity (GO:0008083), matching the curated review. BioReason adds moderate value over interpro2go through the matrix-tethering narrative.

Notes on thinking trace

The trace correctly identifies the PDGF/VEGF domain, cystine-knot superfamily, and heparin-binding domain. The mechanistic model of matrix concentration enhancing receptor clustering is biologically sound. The trace appropriately infers secretion and extracellular localization from the absence of transmembrane domains.

📄 View Raw YAML

id: P15692
gene_symbol: VEGFA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'VEGFA (Vascular Endothelial Growth Factor A) is the master regulator of angiogenesis. CRITICAL ISOFORM BIOLOGY: Alternative splicing produces 17 isoforms with diverse functions: (1) Most isoforms (VEGF121/165/189/206) are PRO-ANGIOGENIC, differing in heparin binding and matrix association - VEGF121 is freely diffusible while VEGF189/206 are matrix-bound; (2) VEGF165B (P15692-8) is ANTI-ANGIOGENIC - it binds VEGFR2 but does NOT activate downstream signaling and INHIBITS tumor growth [PMID:15520188]. All current GOA annotations are for positive angiogenesis regulation - MISSING the anti-angiogenic VEGF165B function. This is a case where isoforms have qualitatively different (even opposite) biological effects.'
existing_annotations:
- term:
    id: GO:0005172
    label: vascular endothelial growth factor receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: VEGFA binds to both VEGFR1 (FLT1) and VEGFR2 (KDR) receptors. This is a core molecular function shared by all VEGFA isoforms including VEGF121, VEGF165, VEGF189, VEGF206, and VEGF165B. The UniProt entry explicitly states binding to FLT1/VEGFR1 and KDR/VEGFR2 receptors. Importantly, even the anti-angiogenic VEGF165B isoform binds to KDR/VEGFR2, though it does not activate downstream signaling. The deep research confirms VEGFA binds to VEGFR1 with approximately 50-fold higher affinity than VEGFR2 [VEGFA-deep-research-perplexity.md].
    action: ACCEPT
    reason: Core molecular function of VEGFA. All isoforms bind VEGF receptors, making this annotation universally applicable to the gene product. Well-supported by IBA phylogenetic inference and extensive experimental literature.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR.
    - reference_id: file:human/VEGFA/VEGFA-deep-research-perplexity.md
      supporting_text: 'provider: perplexity'
- term:
    id: GO:0008083
    label: growth factor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: VEGFA is a canonical growth factor that stimulates endothelial cell proliferation through VEGFR2 signaling. The deep research confirms VEGFA stimulates multiple cellular responses including proliferation, survival, and migration. VEGF165 induces approximately 27% increase in HUVEC proliferation. However, this is true for pro-angiogenic isoforms (VEGF121/165/189/206) but NOT for VEGF165B which lacks mitogenic activity.
    action: ACCEPT
    reason: Core molecular function. Growth factor activity is well-documented for the major pro-angiogenic isoforms. The IBA inference is phylogenetically sound.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:21771332
      supporting_text: VEGF stimulated HUVEC proliferation by 27% relative to untreated cells
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: VEGFA is the canonical ligand that activates VEGF receptor signaling pathways through VEGFR1 and VEGFR2. Binding induces receptor dimerization and autophosphorylation, activating downstream PLCgamma-PKC-MAPK, PI3K-Akt, and p38 MAPK pathways. VEGF165B also binds receptors but initiates only weak signaling insufficient for angiogenic responses [VEGFA-deep-research-perplexity.md].
    action: ACCEPT
    reason: Core biological process. VEGFA is the defining ligand for VEGFR signaling pathways. All isoforms engage receptors, though with different downstream consequences.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'VEGFA is a secreted growth factor that functions in the extracellular space. It contains an N-terminal signal sequence targeting it to the secretory pathway. However, isoform localization varies: VEGF121 is freely diffusible, VEGF165 has intermediate bioavailability, while VEGF189/206 are matrix-bound. Substantial intracrine functions have also been documented [VEGFA-deep-research-perplexity.md].'
    action: ACCEPT
    reason: Core cellular component for the secreted protein. While some intracrine signaling exists, the primary function is as an extracellular signaling molecule.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0038084
    label: vascular endothelial growth factor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This is essentially the same as GO:0048010 (vascular endothelial growth factor receptor signaling pathway). VEGFA is the canonical ligand initiating VEGF signaling through VEGFR1/2 receptors. Both pro-angiogenic and anti-angiogenic isoforms participate in this pathway, though with different outcomes.
    action: ACCEPT
    reason: Core biological process. VEGFA is the defining ligand of the VEGF signaling pathway. Note this term (GO:0038084) is a child of GO:0048010.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:20660291
      supporting_text: gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: VEGFA functions as a chemoattractant for endothelial cells, promoting their directed migration during angiogenesis. It also serves as a chemoattractant for monocytes and macrophages via VEGFR1. The deep research notes VEGF acts as a chemoattractant for endothelial cells and inflammatory cells including macrophages.
    action: ACCEPT
    reason: Core molecular function. Chemoattractant activity is essential for VEGFA's role in angiogenesis and inflammation.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
- term:
    id: GO:0050930
    label: induction of positive chemotaxis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: VEGFA induces positive chemotaxis of endothelial cells towards the VEGF source, essential for directed vessel sprouting during angiogenesis. This is mediated primarily through VEGFR2 signaling and downstream Rac1/Cdc42 activation.
    action: ACCEPT
    reason: Core biological process. Chemotactic guidance of endothelial cells is essential for VEGFA's angiogenic function.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
- term:
    id: GO:0060754
    label: positive regulation of mast cell chemotaxis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: VEGFA can regulate mast cell chemotaxis through VEGFR1 and VEGFR2 expressed on mast cells. This is a peripheral function related to VEGFA's broader roles in inflammation and immune modulation rather than a core angiogenic function.
    action: KEEP_AS_NON_CORE
    reason: While VEGFA does regulate immune cell chemotaxis, mast cell chemotaxis is not a core function. This represents a pleiotropic effect in inflammatory contexts.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0002040
    label: sprouting angiogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'VEGFA is the master regulator of sprouting angiogenesis. It promotes tip cell selection, endothelial cell migration, proliferation, and vessel lumen formation. CRITICAL ISOFORM NOTE: This applies to pro-angiogenic isoforms (VEGF121/165/189/206) but NOT to VEGF165B, which is anti-angiogenic and inhibits sprouting.'
    action: ACCEPT
    reason: Core function for the majority of VEGFA isoforms. While VEGF165B inhibits angiogenesis, the predominant isoforms are pro-angiogenic. The IBA annotation captures the conserved ancestral function. Isoform-specific annotation would require GO annotation extensions.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: VEGFA expression is strongly induced by hypoxia through HIF-1alpha stabilization. This is a key regulatory mechanism ensuring VEGFA is produced when tissues need increased vascularization. The protein itself also has structural adaptations (cystine-knot) enabling proper folding under hypoxic conditions.
    action: ACCEPT
    reason: Core regulatory relationship. Hypoxia-induced VEGFA expression is one of the most well-characterized gene regulatory responses in mammalian biology.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'VEGFA is the master regulator of angiogenesis. This IEA annotation correctly captures the core function. ISOFORM NOTE: Pro-angiogenic isoforms (VEGF121/165/189/206) promote angiogenesis; VEGF165B is anti-angiogenic.'
    action: ACCEPT
    reason: Core biological process. IEA is consistent with extensive experimental evidence. The term is appropriately general for the gene-level annotation.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: VEGFA has roles in immune modulation including macrophage chemotaxis and polarization. However, this term is very broad and over-general for the specific immune functions of VEGFA.
    action: MARK_AS_OVER_ANNOTATED
    reason: While VEGFA does have immune-related functions (macrophage recruitment, M2 polarization), the term "immune system process" is too broad. More specific terms like macrophage chemotaxis would be more informative.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: VEGFA is a secreted growth factor that functions primarily in the extracellular region. Contains an N-terminal signal peptide for secretory pathway targeting.
    action: ACCEPT
    reason: Core cellular component. VEGFA is secreted and functions extracellularly. This is broader than GO:0005615 (extracellular space) but still accurate.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Nuclear-localized VEGF has been detected in multiple cell types as part of intracrine signaling. The deep research notes nuclear VEGF and VEGFR2 participate in direct regulation of gene expression and metabolic homeostasis.
    action: KEEP_AS_NON_CORE
    reason: While nuclear VEGFA exists and has functional significance for intracrine signaling, the primary localization and function is extracellular. Nuclear localization represents a secondary function.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: VEGFA transits through the cytoplasm during synthesis and secretion. Intracrine VEGF signaling also involves cytoplasmic pools of VEGF and its receptors.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is a transit compartment during biosynthesis. The functional localization is extracellular. This is accurate but not a core functional location.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: VEGFA undergoes dimerization and disulfide bond formation in the ER during biosynthesis. The deep research notes that VEGFA can efficiently complete disulfide bond formation in the ER even under hypoxia.
    action: KEEP_AS_NON_CORE
    reason: ER is a transit compartment during biosynthesis, not a functional location. Accurate but represents biosynthetic pathway rather than functional localization.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: VEGFA transits through the Golgi for N-linked glycosylation during secretion. Post-Golgi transport depends on glycosylation modifications.
    action: KEEP_AS_NON_CORE
    reason: Golgi is a transit compartment for secretion, not a functional location. Accurate but represents biosynthetic pathway.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0008083
    label: growth factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: VEGFA is a canonical growth factor stimulating endothelial cell proliferation and survival. This IEA annotation is consistent with the IBA annotation and extensive experimental evidence.
    action: ACCEPT
    reason: Core molecular function. Duplicates IBA annotation but IEA provides independent computational evidence support.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Heparin binding is ISOFORM-SPECIFIC. VEGF121 lacks heparin binding (no exons 6/7). VEGF165 has intermediate heparin affinity (exon 7 only). VEGF189/206 have high heparin affinity (exons 6 and 7). This is a key determinant of bioavailability.
    action: ACCEPT
    reason: Important molecular function, though isoform-specific. The predominant isoforms (VEGF165, VEGF189) do bind heparin. Annotation is valid at gene level.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'VEGFA stimulates endothelial cell proliferation through VEGFR2-PLCgamma-PKC-MAPK signaling. Also promotes proliferation of other cell types. ISOFORM NOTE: VEGF165B does not stimulate proliferation.'
    action: ACCEPT
    reason: Core biological process for pro-angiogenic isoforms. Proliferation is essential for angiogenesis. The term is appropriately general.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: VEGFA associates with the plasma membrane surface before shedding. The deep research notes substantial fraction localizes to outer plasma membrane in punctate pattern.
    action: KEEP_AS_NON_CORE
    reason: Membrane association is transient during secretion. Primary function is extracellular. This InterPro-based annotation is less informative than specific localization terms.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: VEGFA promotes endothelial cell differentiation during vascular development and angiogenesis. However, this term is very broad.
    action: MARK_AS_OVER_ANNOTATED
    reason: While VEGFA affects endothelial cell differentiation, the term is too general. More specific terms like vasculogenesis or endothelial cell differentiation would be more informative.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: VEGFA is a chemoattractant for endothelial cells and monocytes/macrophages. This IEA annotation is consistent with the IBA annotation.
    action: ACCEPT
    reason: Core molecular function. Duplicates IBA but IEA provides independent evidence support.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0043117
    label: positive regulation of vascular permeability
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'VEGFA (originally called Vascular Permeability Factor/VPF) is a potent inducer of vascular permeability through phosphorylation of junctional proteins and Rac1-mediated cytoskeletal changes. ISOFORM NOTE: Pro-angiogenic isoforms only.'
    action: ACCEPT
    reason: Core biological process. VEGFA was originally identified as a permeability factor. This is a defining function of the protein.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0043184
    label: vascular endothelial growth factor receptor 2 binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: VEGFA binds VEGFR2/KDR, the main transducer of angiogenic signals. All isoforms including VEGF165B bind VEGFR2, though with different signaling outcomes.
    action: ACCEPT
    reason: Core molecular function. VEGFR2 binding is essential for VEGFA signaling.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'VEGFA is the master positive regulator of angiogenesis. CRITICAL ISOFORM NOTE: This applies to pro-angiogenic isoforms (VEGF121/165/189/206) but NOT to VEGF165B, which INHIBITS angiogenesis and should have a negative regulation annotation.'
    action: ACCEPT
    reason: Core function for pro-angiogenic isoforms. The annotation correctly captures the predominant function. A separate annotation for VEGF165B anti-angiogenic activity would be needed for completeness.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: VEGFA is the canonical ligand for VEGFR signaling. This IEA annotation is consistent with the IBA annotations for this pathway.
    action: ACCEPT
    reason: Core biological process. Duplicates IBA but provides independent evidence support.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0051781
    label: positive regulation of cell division
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: VEGFA promotes endothelial cell division through MAPK signaling. This is related to its proliferative effects.
    action: ACCEPT
    reason: Valid biological process annotation. Cell division is required for angiogenesis.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10543948
  review:
    summary: Generic protein binding annotation. VEGFA binds multiple proteins including receptors (VEGFR1, VEGFR2, NRP1), matrix components, and coreceptors.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic. More specific binding terms (VEGFR binding, heparin binding) are more informative. This is a common over-annotation pattern.
    supported_by:
    - reference_id: PMID:10543948
      supporting_text: 'Solution structure of the VEGF-binding domain of Flt-1: comparison of its free and bound states.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16763549
  review:
    summary: Generic protein binding annotation based on neuropilin-1 and VEGFR2 interaction studies.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic. The specific interaction partners (NRP1, VEGFR2) warrant more specific GO terms.
    supported_by:
    - reference_id: PMID:16763549
      supporting_text: Jun 8. Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17222790
  review:
    summary: Generic protein binding annotation based on neuropilin-1 interaction studies.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic. Neuropilin binding would be more informative.
    supported_by:
    - reference_id: PMID:17222790
      supporting_text: Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20660291
  review:
    summary: Generic protein binding annotation from Gremlin-VEGFR2 study context.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic.
    supported_by:
    - reference_id: PMID:20660291
      supporting_text: gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21653826
  review:
    summary: Generic protein binding annotation based on NRP1 interaction study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic. NRP1 binding would be more informative.
    supported_by:
    - reference_id: PMID:21653826
      supporting_text: 2011 Jun 8. VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23374253
  review:
    summary: Generic protein binding annotation based on endorepellin-VEGFR2 study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic.
    supported_by:
    - reference_id: PMID:23374253
      supporting_text: Endorepellin laminin-like globular 1/2 domains bind Ig3-5 of vascular endothelial growth factor (VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23583373
  review:
    summary: Generic protein binding annotation based on VEGFR2 interaction study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic. VEGFR2 binding is already annotated specifically.
    supported_by:
    - reference_id: PMID:23583373
      supporting_text: Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Generic protein binding annotation from proteome-scale interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic for high-throughput interactome data.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9393862
  review:
    summary: Generic protein binding annotation from VEGF-Flt1 crystal structure study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic. VEGFR1 binding would be more informative.
    supported_by:
    - reference_id: PMID:9393862
      supporting_text: Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:12207021
  review:
    summary: VEGFA forms homodimers stabilized by interchain disulfide bonds between Cys51 and Cys60. Dimerization is essential for receptor activation.
    action: ACCEPT
    reason: Core molecular function. VEGFA homodimerization is required for biological activity. This is more specific and informative than generic protein binding.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:12207021
      supporting_text: 2002 Aug 30. The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25132001
  review:
    summary: VEGFA homodimerization study. Consistent with the essential role of dimerization in VEGFA function.
    action: ACCEPT
    reason: Core molecular function. Homodimerization is essential for VEGFA activity.
    supported_by:
    - reference_id: PMID:25132001
      supporting_text: Development of a highly-potent anti-angiogenic VEGF8-109 heterodimer by directed blocking of its VEGFR-2 binding site.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate of IBA annotation. VEGFA functions in the extracellular space.
    action: ACCEPT
    reason: Core cellular component. Consistent with IBA annotation.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0010719
    label: negative regulation of epithelial to mesenchymal transition
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transferred from Ensembl ortholog. The role of VEGFA in EMT is complex and context-dependent. In some contexts VEGFA may inhibit EMT but this is not a well-established core function.
    action: UNDECIDED
    reason: EMT regulation by VEGFA is complex. This ortholog-transferred annotation may not reflect human VEGFA function. Requires literature review.
- term:
    id: GO:0031290
    label: retinal ganglion cell axon guidance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: VEGFA has documented roles in neural guidance including retinal development. This is a pleiotropic developmental function beyond core angiogenesis.
    action: KEEP_AS_NON_CORE
    reason: VEGFA has neural guidance functions but this is peripheral to its core angiogenic role. Valid developmental function.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0035924
    label: cellular response to vascular endothelial growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Circular annotation - VEGFA is the stimulus, not the responder. This annotation would be appropriate for VEGF receptors, not VEGFA itself.
    action: REMOVE
    reason: Inappropriate annotation. VEGFA is the ligand that causes the stimulus, not a gene product that responds to VEGF stimulus.
- term:
    id: GO:0048842
    label: positive regulation of axon extension involved in axon guidance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: VEGFA has neural guidance functions including axon extension regulation. This is a pleiotropic developmental function.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0050918
    label: positive chemotaxis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: VEGFA induces positive chemotaxis of endothelial cells and other cell types. Consistent with IBA chemoattractant activity annotation.
    action: ACCEPT
    reason: Core biological process. Chemotaxis is essential for angiogenesis.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0071679
    label: commissural neuron axon guidance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: VEGFA has documented roles in neural guidance. This is a pleiotropic developmental function.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
- term:
    id: GO:0090190
    label: positive regulation of branching involved in ureteric bud morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: VEGFA has roles in kidney development including ureteric bud morphogenesis. This is a pleiotropic developmental function.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
- term:
    id: GO:0097475
    label: motor neuron migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: VEGFA has neural guidance functions. Motor neuron migration may be affected by VEGFA signaling as part of developmental neurovascular coordination.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
- term:
    id: GO:0120162
    label: positive regulation of cold-induced thermogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: VEGFA has documented roles in brown adipose tissue function and thermogenesis. The deep research notes autocrine VEGFA is essential for mitochondrial function in brown adipocytes.
    action: KEEP_AS_NON_CORE
    reason: Valid metabolic function but peripheral to core angiogenic role.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1235037
  review:
    summary: Reactome pathway annotation for VEGFA expression. VEGFA is secreted to the extracellular region.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194310
  review:
    summary: Reactome pathway annotation for VEGF-A,C,D binding to VEGFR2.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194311
  review:
    summary: Reactome pathway annotation for VEGFA,B,PLGF binding to VEGFR1.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-195378
  review:
    summary: Reactome pathway annotation for homodimerization of VEGF proteins.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420083
  review:
    summary: Reactome pathway annotation for PTK2 recruitment to VEGFR2 signaling complex.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420099
  review:
    summary: Reactome pathway annotation for VEGFR2-SHB binding.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420107
  review:
    summary: Reactome pathway annotation for VEGFR2-SHC2 binding.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420117
  review:
    summary: Reactome pathway annotation for VEGFR2 autophosphorylation.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420121
  review:
    summary: Reactome pathway annotation for SFK phosphorylation of PLCgamma1.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420128
  review:
    summary: Reactome pathway annotation for SRC-1 phosphorylation of SHB.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420140
  review:
    summary: Reactome pathway annotation for SRC-1 recruitment to VEGFR2.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420143
  review:
    summary: Reactome pathway annotation for VEGFR2-SH2D2A binding.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420153
  review:
    summary: Reactome pathway annotation for VEGFR2-PLCgamma1 binding.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420202
  review:
    summary: Reactome pathway annotation for PLCgamma1 translocation to plasma membrane.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4420206
  review:
    summary: Reactome pathway annotation. VEGFA is secreted extracellularly.
    action: ACCEPT
    reason: Core cellular component. Consistent with other annotations.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: Reactome pathway annotation for platelet degranulation.
    action: ACCEPT
    reason: Core cellular component. VEGFA is released during platelet degranulation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218640
  review:
    summary: Reactome pathway annotation for NRP1-VEGF binding.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218642
  review:
    summary: Reactome pathway annotation for NRP1-VEGFR signaling complex.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218643
  review:
    summary: Reactome pathway annotation for VEGF signaling.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218645
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218804
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218806
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218809
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218811
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218812
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218814
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218815
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218818
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218819
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218820
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218822
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218824
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218826
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218830
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218832
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218836
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218838
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218839
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218847
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218851
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218854
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5357429
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5357432
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5357479
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6789615
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8864936
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9679477
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9691215
  review:
    summary: Reactome pathway annotation.
    action: ACCEPT
    reason: Core cellular component.
- term:
    id: GO:0031093
    label: platelet alpha granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: VEGFA is stored in platelet alpha granules and released during platelet degranulation. This contributes to wound healing and vascular repair.
    action: ACCEPT
    reason: Valid cellular component. Platelet storage is a documented function.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0038084
    label: vascular endothelial growth factor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:20660291
  review:
    summary: Experimental study demonstrating VEGFA activates VEGFR2 signaling. The paper identifies gremlin as a novel VEGFR2 agonist distinct from VEGF family ligands, validating VEGFA as the canonical VEGFR2 ligand.
    action: ACCEPT
    reason: Core biological process. IDA evidence from direct experimental demonstration.
    supported_by:
    - reference_id: PMID:20660291
      supporting_text: gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:21771332
  review:
    summary: Study comparing VEGF and leptin effects on endothelial cells. VEGF (50 ng/mL) stimulated HUVEC proliferation by 27% and tube formation by ~60%. This directly demonstrates VEGFA angiogenic activity.
    action: ACCEPT
    reason: Core biological process with direct experimental evidence.
    supported_by:
    - reference_id: PMID:21771332
      supporting_text: VEGF stimulated HUVEC proliferation by 27% relative to untreated cells
- term:
    id: GO:0001569
    label: branching involved in blood vessel morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:23688497
  review:
    summary: IMP evidence for VEGFA role in blood vessel branching morphogenesis. Publication not in cache - based on annotation appears to demonstrate VEGFA involvement in vessel branching.
    action: UNDECIDED
    reason: Publication PMID:23688497 not available for verification. Blood vessel branching is consistent with known VEGFA functions.
    supported_by:
    - reference_id: PMID:23688497
      supporting_text: Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:31915155
  review:
    summary: IDA evidence for VEGFA stimulating endothelial cell proliferation. Function is well-established from multiple other sources.
    action: ACCEPT
    reason: Core function. Function is well-established from multiple IDA and IBA sources; additional IDA evidence is consistent.
    supported_by:
    - reference_id: PMID:31915155
      supporting_text: PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.
- term:
    id: GO:0038033
    label: positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:31915155
  review:
    summary: Very specific GO term capturing VEGFA-induced endothelial chemotaxis via VEGFR signaling. This is consistent with established VEGFA function.
    action: UNDECIDED
    reason: Publication PMID:31915155 not available for verification. Function is consistent with known biology but specific evidence cannot be confirmed.
    supported_by:
    - reference_id: PMID:31915155
      supporting_text: PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:11461089
  review:
    summary: IMP evidence for VEGFA anti-apoptotic function. VEGFA promotes endothelial cell survival through PI3K-Akt signaling pathway.
    action: ACCEPT
    reason: Core function. Anti-apoptotic function is well-established from deep research documenting Akt-mediated survival signaling. Consistent with other IMP evidence.
    supported_by:
    - reference_id: PMID:11461089
      supporting_text: Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells.
- term:
    id: GO:1900748
    label: positive regulation of vascular endothelial growth factor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:23688497
  review:
    summary: Autocrine/positive feedback annotation for VEGFA on its own signaling pathway. VEGFA can amplify its own signaling through various mechanisms.
    action: UNDECIDED
    reason: Publication PMID:23688497 not available for verification.
    supported_by:
    - reference_id: PMID:23688497
      supporting_text: Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
- term:
    id: GO:1905555
    label: positive regulation of blood vessel branching
  evidence_type: IDA
  original_reference_id: PMID:20123964
  review:
    summary: IDA evidence for VEGFA promoting vessel branching. Publication not in cache. Vessel branching is a core VEGFA angiogenic function.
    action: UNDECIDED
    reason: Publication PMID:20123964 not available for verification.
    supported_by:
    - reference_id: PMID:20123964
      supporting_text: Feb 1. Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
- term:
    id: GO:0038084
    label: vascular endothelial growth factor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:19148554
  review:
    summary: IMP evidence for VEGFA in VEGF signaling pathway. Core function established from multiple sources.
    action: ACCEPT
    reason: Core biological process. VEGFA is the canonical ligand for VEGF signaling; function is well-established from IBA and other IDA sources.
    supported_by:
    - reference_id: PMID:19148554
      supporting_text: Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.
- term:
    id: GO:0007200
    label: phospholipase C-activating G protein-coupled receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18059339
  review:
    summary: VEGFA activates PLCgamma through VEGFR2 signaling. The study shows VEGF signals through PKC pathway to activate transcription factor Egr3.
    action: ACCEPT
    reason: Core signaling mechanism. VEGFR2-PLCgamma-PKC is a major VEGFA signaling pathway.
    supported_by:
    - reference_id: PMID:18059339
      supporting_text: VEGF induced a rapid increase in Egr-dependent transcriptional activation mediated via its major signalling receptor, VEGFR2/KDR, and the protein kinase C (PKC) pathway
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: IDA
  original_reference_id: PMID:18059339
  review:
    summary: VEGFA promotes endothelial cell migration. The study demonstrates VEGF mediates endothelial cell migration and tubulogenesis through Egr3.
    action: ACCEPT
    reason: Core molecular function. Direct experimental evidence for chemoattractant activity.
    supported_by:
    - reference_id: PMID:18059339
      supporting_text: Inhibition of Egr3 gene expression by RNA interference was effective in inhibiting basal and VEGF-induced Egr3 gene expression, and it also inhibited VEGF-mediated endothelial cell proliferation, migration and tubulogenesis
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18059339
  review:
    summary: Direct evidence that VEGF signals through VEGFR2/KDR to activate PKC pathway.
    action: ACCEPT
    reason: Core biological process with direct experimental evidence.
    supported_by:
    - reference_id: PMID:18059339
      supporting_text: VEGF induced a rapid increase in Egr-dependent transcriptional activation mediated via its major signalling receptor, VEGFR2/KDR, and the protein kinase C (PKC) pathway
- term:
    id: GO:0035767
    label: endothelial cell chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: Study shows VEGF induces endothelial cell migration through PKD-HSP27 pathway. Knockdown of HSP27 and PKDs markedly inhibited VEGF-induced HUVEC migration.
    action: ACCEPT
    reason: Core biological process with direct experimental evidence for chemotaxis mechanism.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: Knockdown of HSP27 and PKDs markedly inhibited VEGF-induced HUVEC migration and tubulogenesis
- term:
    id: GO:0035767
    label: endothelial cell chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:21245381
  review:
    summary: IDA evidence for VEGFA-induced endothelial cell chemotaxis. Consistent with other experimental evidence.
    action: ACCEPT
    reason: Core function. Endothelial cell chemotaxis is well-established from multiple IDA sources including PMID:18440775.
    supported_by:
    - reference_id: PMID:21245381
      supporting_text: Jan 18. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: VEGF activates MAPK cascade through VEGFR2 signaling. The study demonstrates VEGF-induced PKD activation leads to downstream signaling including ERK/MAPK.
    action: ACCEPT
    reason: Core signaling pathway. VEGFR2-PLCgamma-PKC-ERK is a major VEGFA signaling cascade.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: VEGF activated Protein Kinase D (PKD) via PKC
- term:
    id: GO:0043536
    label: positive regulation of blood vessel endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: VEGF promotes endothelial cell migration. Study shows PKD-HSP27 pathway mediates VEGF-induced migration and tubulogenesis.
    action: ACCEPT
    reason: Core biological process. Essential for angiogenesis.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: Knockdown of HSP27 and PKDs markedly inhibited VEGF-induced HUVEC migration and tubulogenesis
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: 'VEGF promotes angiogenesis. Study shows VEGF-induced tubulogenesis via PKD-HSP27 pathway. CRITICAL ISOFORM NOTE: Applies to pro-angiogenic isoforms only; VEGF165B is anti-angiogenic.'
    action: ACCEPT
    reason: Core biological process for pro-angiogenic isoforms.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: PKDs and HSP27 play major roles in the angiogenic response to VEGF
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: VEGF signals through VEGFR2/KDR. Study demonstrates VEGF-induced signaling through PKD pathway.
    action: ACCEPT
    reason: Core biological process.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:21245381
  review:
    summary: IDA evidence for VEGFR signaling. Core function supported by multiple independent references.
    action: ACCEPT
    reason: Core function. VEGFR signaling is well-established from multiple sources; additional IDA evidence consistent.
    supported_by:
    - reference_id: PMID:21245381
      supporting_text: Jan 18. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.
- term:
    id: GO:0090050
    label: positive regulation of cell migration involved in sprouting angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:18059339
  review:
    summary: VEGF promotes cell migration in sprouting angiogenesis through Egr3-mediated transcriptional regulation.
    action: ACCEPT
    reason: Core biological process.
    supported_by:
    - reference_id: PMID:18059339
      supporting_text: it also inhibited VEGF-mediated endothelial cell proliferation, migration and tubulogenesis
- term:
    id: GO:0031290
    label: retinal ganglion cell axon guidance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for neural guidance function. VEGFA has documented roles in neurovascular coordination.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
- term:
    id: GO:0038190
    label: VEGF-activated neuropilin signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA binds neuropilin-1 (VEGF165 isoform specifically through exon 7). NRP1 serves as a co-receptor enhancing VEGFR2 signaling.
    action: ACCEPT
    reason: Important signaling pathway, especially for VEGF165 isoform.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation consistent with IBA and IDA evidence.
    action: ACCEPT
    reason: Core molecular function. Multiple evidence sources support this.
- term:
    id: GO:0048842
    label: positive regulation of axon extension involved in axon guidance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for neural guidance function.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
- term:
    id: GO:0050918
    label: positive chemotaxis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation consistent with IEA evidence.
    action: ACCEPT
    reason: Core biological process.
- term:
    id: GO:0071679
    label: commissural neuron axon guidance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for neural guidance function.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:19652095
  review:
    summary: IMP evidence for VEGFA regulation of transcription. Publication not in cache. VEGFA signaling is known to activate various transcription factors.
    action: UNDECIDED
    reason: Publication PMID:19652095 not available for verification.
    supported_by:
    - reference_id: PMID:19652095
      supporting_text: Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IMP
  original_reference_id: PMID:19652095
  review:
    summary: IMP evidence for VEGFA in hypoxia response. VEGFA expression is induced by hypoxia, and it also participates in cellular responses to low oxygen.
    action: UNDECIDED
    reason: Publication PMID:19652095 not available for verification.
    supported_by:
    - reference_id: PMID:19652095
      supporting_text: Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor.
- term:
    id: GO:0038084
    label: vascular endothelial growth factor signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:23878390
  review:
    summary: NAS (non-traceable author statement) evidence. Consistent with core function.
    action: ACCEPT
    reason: Core biological process. VEGFA is the canonical ligand.
    supported_by:
    - reference_id: PMID:23878390
      supporting_text: Jul 22. MicroRNA 329 suppresses angiogenesis by targeting CD146.
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: NAS
  original_reference_id: PMID:23878390
  review:
    summary: NAS evidence for VEGFA activation of NF-kappaB signaling. VEGFA can activate NF-kappaB through various pathways in endothelial and cancer cells.
    action: KEEP_AS_NON_CORE
    reason: Valid signaling pathway but not core to angiogenic function.
    supported_by:
    - reference_id: PMID:23878390
      supporting_text: Jul 22. MicroRNA 329 suppresses angiogenesis by targeting CD146.
- term:
    id: GO:1902894
    label: negative regulation of miRNA transcription
  evidence_type: NAS
  original_reference_id: PMID:23878390
  review:
    summary: NAS evidence for VEGFA regulation of miRNA transcription. VEGFA signaling can modulate miRNA expression as part of broader transcriptional effects.
    action: KEEP_AS_NON_CORE
    reason: Secondary regulatory effect rather than core function.
    supported_by:
    - reference_id: PMID:23878390
      supporting_text: Jul 22. MicroRNA 329 suppresses angiogenesis by targeting CD146.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: IDA evidence for VEGFA stimulating EC proliferation. Core function well-established.
    action: ACCEPT
    reason: Core function. Function is well-established from multiple IDA and IBA sources.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0030297
    label: transmembrane receptor protein tyrosine kinase activator activity
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: VEGFA activates VEGFR1 and VEGFR2, which are receptor tyrosine kinases. This is the core molecular function of VEGFA as a ligand.
    action: ACCEPT
    reason: Core molecular function. VEGFA activates VEGFR tyrosine kinase activity.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0035924
    label: cellular response to vascular endothelial growth factor stimulus
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: Circular annotation - VEGFA is the stimulus, not the responder. This annotation would be appropriate for VEGF receptors or downstream effectors, not VEGFA itself.
    action: REMOVE
    reason: Inappropriate annotation. VEGFA is the ligand that causes the stimulus, not a gene product that responds to VEGF stimulus.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0043536
    label: positive regulation of blood vessel endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: IDA evidence for VEGFA promoting EC migration. Core function well-established.
    action: ACCEPT
    reason: Core function. EC migration is well-established from multiple IDA sources.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: IDA evidence for VEGFA regulating transcription. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:20497126 not available.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:20497126
  review:
    summary: IMP evidence for VEGFR signaling. Core function supported by multiple independent references.
    action: ACCEPT
    reason: Core function. VEGFR signaling is well-established from multiple sources; additional IMP evidence consistent.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:2001028
    label: positive regulation of endothelial cell chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: VEGFA induces endothelial cell chemotaxis. This is consistent with chemoattractant activity and sprouting angiogenesis function.
    action: UNDECIDED
    reason: Publication PMID:20497126 not available. Function consistent with other evidence.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0038084
    label: vascular endothelial growth factor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23083510
  review:
    summary: IMP evidence for VEGF signaling. Core function established from multiple sources.
    action: ACCEPT
    reason: Core biological process. VEGFA is the canonical ligand for VEGF signaling.
    supported_by:
    - reference_id: PMID:23083510
      supporting_text: miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IMP
  original_reference_id: PMID:23083510
  review:
    summary: VEGFA is a receptor ligand for VEGFR1, VEGFR2, and neuropilins. This is a core molecular function.
    action: ACCEPT
    reason: Core molecular function. VEGFA is the canonical VEGFR ligand.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:23083510
      supporting_text: miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
- term:
    id: GO:0036324
    label: vascular endothelial growth factor receptor-2 signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23688497
  review:
    summary: VEGFA activates VEGFR2 signaling. This is the primary signaling receptor for angiogenic effects.
    action: ACCEPT
    reason: Core biological process. VEGFR2 is the main angiogenic signaling receptor.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:23688497
      supporting_text: Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17446437
  review:
    summary: Generic protein binding annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic. More specific binding terms are more informative.
    supported_by:
    - reference_id: PMID:17446437
      supporting_text: 'Epub 2007 Apr 19. Association of ATP1A1 and dear single-nucleotide polymorphism haplotypes with essential hypertension: sex-specific and haplotype-specific effects.'
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:28977001
  review:
    summary: IDA evidence for VEGFA negative regulation of gene expression. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:28977001 not available.
    supported_by:
    - reference_id: PMID:28977001
      supporting_text: eCollection 2017. MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25825981
  review:
    summary: Generic protein binding annotation from EMMPRIN study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is too generic.
    supported_by:
    - reference_id: PMID:25825981
      supporting_text: EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.
- term:
    id: GO:0043184
    label: vascular endothelial growth factor receptor 2 binding
  evidence_type: IPI
  original_reference_id: PMID:25825981
  review:
    summary: VEGFA binds VEGFR2. Core molecular function shared by all VEGFA isoforms.
    action: ACCEPT
    reason: Core molecular function.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:25825981
      supporting_text: EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:1312256
  review:
    summary: Early IDA evidence for VEGFR signaling. This paper identified Flt-1 as a VEGF receptor.
    action: ACCEPT
    reason: Core function. Historic paper identifying VEGFR1/Flt-1 as VEGF receptor; VEGFR signaling is well-established.
    supported_by:
    - reference_id: PMID:1312256
      supporting_text: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
- term:
    id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:7929439
  review:
    summary: Classic paper demonstrating VEGF signals through KDR (VEGFR2). Shows VEGF induces chemotaxis and mitogenicity in KDR-expressing cells.
    action: ACCEPT
    reason: Core biological process with landmark experimental evidence.
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
- term:
    id: GO:0043536
    label: positive regulation of blood vessel endothelial cell migration
  evidence_type: IMP
  original_reference_id: PMID:23688497
  review:
    summary: IMP evidence for EC migration. Core function well-established.
    action: ACCEPT
    reason: Core function. EC migration is well-established from multiple IDA sources.
    supported_by:
    - reference_id: PMID:23688497
      supporting_text: Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
- term:
    id: GO:0061042
    label: vascular wound healing
  evidence_type: IMP
  original_reference_id: PMID:23688497
  review:
    summary: VEGFA promotes wound healing through stimulation of angiogenesis. This is a physiological context for VEGFA angiogenic function.
    action: ACCEPT
    reason: Valid biological process. Wound healing is a key physiological context for angiogenesis.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:23688497
      supporting_text: Epub 2013 May 17. MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
- term:
    id: GO:1903589
    label: positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:30106099
  review:
    summary: IMP evidence for sprouting angiogenesis. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:30106099 not available.
    supported_by:
    - reference_id: PMID:30106099
      supporting_text: Aug 6. Overexpression of miR‑21 is involved in acute monocytic leukemia‑associated angiogenesis by targeting IL‑12.
- term:
    id: GO:0001569
    label: branching involved in blood vessel morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:23083510
  review:
    summary: IMP evidence for vessel branching. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:23083510 not available.
    supported_by:
    - reference_id: PMID:23083510
      supporting_text: miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
- term:
    id: GO:0090050
    label: positive regulation of cell migration involved in sprouting angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:23083510
  review:
    summary: IMP evidence for migration in sprouting angiogenesis. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:23083510 not available.
    supported_by:
    - reference_id: PMID:23083510
      supporting_text: miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
- term:
    id: GO:1901165
    label: positive regulation of trophoblast cell migration
  evidence_type: IMP
  original_reference_id: PMID:23083510
  review:
    summary: VEGFA promotes trophoblast migration during placental development. This is a developmental function beyond core angiogenesis.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
    supported_by:
    - reference_id: PMID:23083510
      supporting_text: miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:19148554
  review:
    summary: IMP evidence for gene expression regulation. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:19148554 not available.
    supported_by:
    - reference_id: PMID:19148554
      supporting_text: Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.
- term:
    id: GO:1905604
    label: negative regulation of blood-brain barrier permeability
  evidence_type: IMP
  original_reference_id: PMID:19148554
  review:
    summary: VEGFA effects on BBB are complex. It can both increase and decrease permeability depending on context and isoform.
    action: UNDECIDED
    reason: Publication PMID:19148554 not available. BBB effects are context-dependent.
    supported_by:
    - reference_id: PMID:19148554
      supporting_text: Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.
- term:
    id: GO:0005912
    label: adherens junction
  evidence_type: IDA
  original_reference_id: PMID:26598555
  review:
    summary: VEGFA affects adherens junction organization as part of permeability regulation. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:26598555 not available.
    supported_by:
    - reference_id: PMID:26598555
      supporting_text: VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
- term:
    id: GO:0043117
    label: positive regulation of vascular permeability
  evidence_type: IDA
  original_reference_id: PMID:26598555
  review:
    summary: 'VEGFA (originally VPF) is a potent inducer of vascular permeability. This is a core function. ISOFORM NOTE: Pro-angiogenic isoforms only.'
    action: ACCEPT
    reason: Core biological process. VEGFA was originally identified as VPF.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:26598555
      supporting_text: VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
- term:
    id: GO:1903392
    label: negative regulation of adherens junction organization
  evidence_type: IDA
  original_reference_id: PMID:26598555
  review:
    summary: VEGFA disrupts adherens junctions to increase permeability. Mechanism involves VE-cadherin phosphorylation and internalization.
    action: ACCEPT
    reason: Part of permeability regulation mechanism.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:26598555
      supporting_text: VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
- term:
    id: GO:2000048
    label: negative regulation of cell-cell adhesion mediated by cadherin
  evidence_type: IDA
  original_reference_id: PMID:26598555
  review:
    summary: VEGFA promotes VE-cadherin internalization reducing cell-cell adhesion. Part of permeability regulation.
    action: ACCEPT
    reason: Part of permeability regulation mechanism.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:26598555
      supporting_text: VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
- term:
    id: GO:1903141
    label: negative regulation of establishment of endothelial barrier
  evidence_type: IDA
  original_reference_id: PMID:20048167
  review:
    summary: VEGFA disrupts endothelial barrier function to increase permeability. Related to VPF activity.
    action: ACCEPT
    reason: Core function related to vascular permeability factor activity.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:20048167
      supporting_text: 2010 Jan 4. Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers.
- term:
    id: GO:0120162
    label: positive regulation of cold-induced thermogenesis
  evidence_type: ISS
  original_reference_id: PMID:26683794
  review:
    summary: VEGFA has roles in brown adipose tissue thermogenesis. ISS evidence from mouse studies.
    action: KEEP_AS_NON_CORE
    reason: Valid metabolic function but peripheral to core angiogenic role.
    supported_by:
    - reference_id: PMID:26683794
      supporting_text: 2015 Sep 25. Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes.
- term:
    id: GO:0010749
    label: regulation of nitric oxide mediated signal transduction
  evidence_type: IDA
  original_reference_id: PMID:16150726
  review:
    summary: VEGFA activates eNOS to produce NO, a key mediator of vascular relaxation and permeability.
    action: ACCEPT
    reason: Important signaling mechanism for VEGFA vascular effects.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:16150726
      supporting_text: Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner.
- term:
    id: GO:0097533
    label: cellular stress response to acid chemical
  evidence_type: IDA
  original_reference_id: PMID:26299712
  review:
    summary: IDA evidence for acid stress response. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:26299712 not available.
    supported_by:
    - reference_id: PMID:26299712
      supporting_text: High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.
- term:
    id: GO:1903672
    label: positive regulation of sprouting angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:26299712
  review:
    summary: VEGFA is the master regulator of sprouting angiogenesis. Publication not in cache.
    action: ACCEPT
    reason: Core biological process. Consistent with extensive evidence.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
    supported_by:
    - reference_id: PMID:26299712
      supporting_text: High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.
- term:
    id: GO:1903672
    label: positive regulation of sprouting angiogenesis
  evidence_type: IGI
  original_reference_id: PMID:25251394
  review:
    summary: IGI evidence for sprouting angiogenesis. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:25251394 not available.
    supported_by:
    - reference_id: PMID:25251394
      supporting_text: eCollection 2014. MicroRNA-377 regulates mesenchymal stem cell-induced angiogenesis in ischemic hearts by targeting VEGF.
- term:
    id: GO:0090050
    label: positive regulation of cell migration involved in sprouting angiogenesis
  evidence_type: IGI
  original_reference_id: PMID:24844779
  review:
    summary: IGI evidence for migration in sprouting angiogenesis. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:24844779 not available.
    supported_by:
    - reference_id: PMID:24844779
      supporting_text: Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
- term:
    id: GO:1903589
    label: positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
  evidence_type: IGI
  original_reference_id: PMID:24844779
  review:
    summary: IGI evidence for EC proliferation in sprouting. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:24844779 not available.
    supported_by:
    - reference_id: PMID:24844779
      supporting_text: Epub 2014 Jul 29. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
- term:
    id: GO:0090050
    label: positive regulation of cell migration involved in sprouting angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:24865854
  review:
    summary: IMP evidence for migration in sprouting. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:24865854 not available.
    supported_by:
    - reference_id: PMID:24865854
      supporting_text: eCollection 2014. Dysregulated miR-361-5p/VEGF axis in the plasma and endothelial progenitor cells of patients with coronary artery disease.
- term:
    id: GO:0097475
    label: motor neuron migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for neural guidance function.
    action: KEEP_AS_NON_CORE
    reason: Valid developmental function but peripheral to core angiogenic role.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:26268439
  review:
    summary: VEGFA stimulates cell proliferation through VEGFR2-PLCgamma-PKC-MAPK signaling. Core function for pro-angiogenic isoforms.
    action: ACCEPT
    reason: Core biological process. Deep research confirms VEGFA promotes endothelial cell proliferation. Pro-angiogenic isoforms only; VEGF165b lacks mitogenic activity.
    supported_by:
    - reference_id: PMID:26268439
      supporting_text: p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.
- term:
    id: GO:0001934
    label: positive regulation of protein phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:19033661
  review:
    summary: VEGFA binding to VEGFR2 induces receptor autophosphorylation and downstream phosphorylation cascades.
    action: ACCEPT
    reason: Core function. VEGFR2 autophosphorylation at Y1175, Y951, Y1214 initiates downstream signaling cascades (deep research).
    supported_by:
    - reference_id: PMID:19033661
      supporting_text: AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
- term:
    id: GO:0010595
    label: positive regulation of endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:19033661
  review:
    summary: VEGFA promotes endothelial cell migration through Y1214-NCK-p38 MAPK pathway and actin remodeling.
    action: ACCEPT
    reason: Core function for angiogenesis. Deep research confirms VEGF induces chemotaxis and directed migration via Rac1/Cdc42 activation.
    supported_by:
    - reference_id: PMID:19033661
      supporting_text: AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
- term:
    id: GO:0031334
    label: positive regulation of protein-containing complex assembly
  evidence_type: IDA
  original_reference_id: PMID:19033661
  review:
    summary: VEGFA signaling may promote assembly of focal adhesion complexes during cell migration.
    action: KEEP_AS_NON_CORE
    reason: Supporting function. VEGF promotes focal adhesion turnover via FAK/paxillin pathway (deep research), but this is downstream of core angiogenic function.
    supported_by:
    - reference_id: PMID:19033661
      supporting_text: AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
- term:
    id: GO:0035148
    label: tube formation
  evidence_type: IDA
  original_reference_id: PMID:19033661
  review:
    summary: VEGFA is essential for vascular tube formation/tubulogenesis during angiogenesis.
    action: ACCEPT
    reason: Core function. Deep research extensively documents VEGF role in vasculogenic tubulogenesis and lumen formation.
    supported_by:
    - reference_id: PMID:19033661
      supporting_text: AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:19033661
  review:
    summary: VEGFA is the master regulator of angiogenesis. ISOFORM NOTE - applies to pro-angiogenic isoforms; VEGF165b is anti-angiogenic.
    action: ACCEPT
    reason: Core function for pro-angiogenic isoforms. Deep research describes VEGFA as "master regulator of angiogenesis."
    supported_by:
    - reference_id: PMID:19033661
      supporting_text: AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
- term:
    id: GO:0008083
    label: growth factor activity
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: VEGFA is a canonical growth factor inducing cell proliferation via VEGFR2 signaling.
    action: ACCEPT
    reason: Core molecular function. VEGFA functions as a homodimeric growth factor (PMID:7929439, deep research).
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0035924
    label: cellular response to vascular endothelial growth factor stimulus
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: Circular annotation - VEGFA IS the stimulus, not the responder. This annotation is logically problematic.
    action: REMOVE
    reason: Circular annotation. VEGFA is the stimulus, not a gene responding to VEGF stimulus. This annotation should be on VEGF-responsive genes, not VEGFA itself.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: VEGFA is a chemoattractant for endothelial cells and monocytes/macrophages.
    action: ACCEPT
    reason: Core molecular function. Deep research and PMID:7929439 confirm VEGFA induces chemotaxis in endothelial cells and macrophages.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0050918
    label: positive chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: VEGFA induces positive chemotaxis in endothelial cells and other cell types.
    action: ACCEPT
    reason: Core biological process. PMID:7929439 shows VEGF induces chemotaxis in KDR-expressing cells.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22020326
  review:
    summary: Generic protein binding term is uninformative. VEGFA binds specifically to VEGFRs, neuropilins, heparin, fibronectin.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative term. More specific terms like VEGFR binding, heparin binding capture the actual binding functions. Generic "protein binding" adds no useful information.
    supported_by:
    - reference_id: PMID:22020326
      supporting_text: MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:18093989
  review:
    summary: VEGF signaling can modulate transcription. Publication not in cache for verification.
    action: UNDECIDED
    reason: Publication PMID:18093989 not available in cache. Cannot verify specific transcriptional regulatory mechanism.
    supported_by:
    - reference_id: PMID:18093989
      supporting_text: Dec 18. Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling.
- term:
    id: GO:0001541
    label: ovarian follicle development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in ovarian follicle development through vascularization. ISS from mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. VEGFA provides vascular support for follicle development but this is secondary to core angiogenic function.
- term:
    id: GO:0001701
    label: in utero embryonic development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA essential for embryonic vascular development. ISS from mouse studies showing embryonic lethality.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. VEGFA is essential for embryonic development primarily through its role in vascular formation. Deep research notes VEGFR2 null mice die at E8.5.
- term:
    id: GO:0001822
    label: kidney development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA important for kidney vascular development. ISS from mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. VEGFA supports kidney development through angiogenesis. Deep research mentions isoform-specific kidney defects.
- term:
    id: GO:0002052
    label: positive regulation of neuroblast proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA has neuroprotective and neuroproliferative effects beyond angiogenesis.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. VEGFA has documented effects on neural cells but this is not a core function.
- term:
    id: GO:0003007
    label: heart morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA essential for cardiac vascular development. ISS from mouse studies.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Deep research notes VEGF-dependent cardiovascular morphogenesis starting at E7.5-8.0 in mice.
- term:
    id: GO:0003151
    label: outflow tract morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in cardiac outflow tract development through vascularization. ISS from mouse.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Secondary to core angiogenic function.
- term:
    id: GO:0003169
    label: coronary vein morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in coronary vessel development. ISS from mouse studies.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Deep research mentions coronary vein morphogenesis defects in VEGF isoform-specific mice.
- term:
    id: GO:0007498
    label: mesoderm development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA expressed during mesodermal development supporting vascular formation.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. VEGF is expressed in mesoderm but function is through vascularization.
- term:
    id: GO:0007595
    label: lactation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in mammary gland vascularization during lactation.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic physiological process. Secondary to angiogenic function.
- term:
    id: GO:0030324
    label: lung development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA essential for lung vascular development. Defects seen in isoform-specific mice.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Deep research notes lung defects in VEGF120/120 mice.
- term:
    id: GO:0030855
    label: epithelial cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA may affect epithelial differentiation through paracrine effects.
    action: MARK_AS_OVER_ANNOTATED
    reason: Indirect effect. VEGFA primarily acts on endothelial cells; effects on epithelium are likely secondary/paracrine.
- term:
    id: GO:0031077
    label: post-embryonic camera-type eye development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in retinal vascular development.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Deep research notes retinal defects in isoform-specific VEGF mice.
- term:
    id: GO:0036303
    label: lymph vessel morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA may have limited role in lymphangiogenesis; VEGF-C/VEGFR3 is primary pathway.
    action: MARK_AS_OVER_ANNOTATED
    reason: VEGF-C and VEGFR3 are the primary lymphangiogenic factors. VEGFA role in lymphangiogenesis is minor compared to its role in blood vessel angiogenesis.
- term:
    id: GO:0042462
    label: eye photoreceptor cell development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA may affect photoreceptor development through retinal vascularization.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Likely indirect effect through retinal vascularization.
- term:
    id: GO:0043129
    label: surfactant homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA may affect lung surfactant through pulmonary vascular development.
    action: MARK_AS_OVER_ANNOTATED
    reason: Indirect effect. This is likely a secondary consequence of VEGFA role in lung vascular development, not a direct function.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:18093989
  review:
    summary: VEGF signaling activates transcription factors that regulate gene expression. Publication not in cache.
    action: UNDECIDED
    reason: Publication PMID:18093989 not available in cache. Cannot verify specific transcriptional mechanism.
    supported_by:
    - reference_id: PMID:18093989
      supporting_text: Dec 18. Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling.
- term:
    id: GO:0048469
    label: cell maturation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA may affect cell maturation in various tissues through vascularization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general. Cell maturation effects are likely indirect through vascular support.
- term:
    id: GO:0048593
    label: camera-type eye morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in eye vascular development.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. VEGFA contributes to eye development through vascularization.
- term:
    id: GO:0048844
    label: artery morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA essential for arterial vessel development.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process related to core angiogenic function. Deep research mentions artery defects in isoform-specific mice.
- term:
    id: GO:0050679
    label: positive regulation of epithelial cell proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA primarily acts on endothelial cells; epithelial effects are secondary.
    action: MARK_AS_OVER_ANNOTATED
    reason: Indirect effect. VEGFA primarily stimulates endothelial cell proliferation, not epithelial.
- term:
    id: GO:0055013
    label: cardiac muscle cell development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA supports cardiac development through vascularization.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. VEGFA affects cardiomyocyte development indirectly through coronary vascularization.
- term:
    id: GO:0060319
    label: primitive erythrocyte differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA may affect primitive erythropoiesis during early development.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. VEGFA expressed in yolk sac during primitive hematopoiesis.
- term:
    id: GO:0060749
    label: mammary gland alveolus development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA supports mammary gland development through vascularization.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Indirect effect through vascular support.
- term:
    id: GO:0060948
    label: cardiac vascular smooth muscle cell development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in coronary vascular smooth muscle development.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process related to cardiac vascular development.
- term:
    id: GO:0060982
    label: coronary artery morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA essential for coronary artery development.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Deep research mentions coronary artery defects in isoform-specific mice.
- term:
    id: GO:0071542
    label: dopaminergic neuron differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA has neuroprotective effects but primary function is angiogenic.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. VEGFA has documented neurotrophic effects but this is not core function.
- term:
    id: GO:0090190
    label: positive regulation of branching involved in ureteric bud morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA involved in kidney/ureteric bud development through vascularization.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic developmental process. Effect on ureteric bud likely through supporting vascularization.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:16489009
  review:
    summary: VEGFA stimulates endothelial cell proliferation. Core function for pro-angiogenic isoforms.
    action: ACCEPT
    reason: Core function. Multiple lines of evidence support VEGFA-induced endothelial proliferation through VEGFR2 signaling.
    supported_by:
    - reference_id: PMID:16489009
      supporting_text: Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein.
- term:
    id: GO:0051894
    label: positive regulation of focal adhesion assembly
  evidence_type: IDA
  original_reference_id: PMID:16489009
  review:
    summary: VEGFA signaling promotes focal adhesion assembly during endothelial cell migration.
    action: KEEP_AS_NON_CORE
    reason: Supporting function for cell migration. Deep research notes FAK/paxillin pathway involvement.
    supported_by:
    - reference_id: PMID:16489009
      supporting_text: Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein.
- term:
    id: GO:0002042
    label: cell migration involved in sprouting angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:20660291
  review:
    summary: VEGFA is essential for endothelial cell migration during sprouting angiogenesis.
    action: ACCEPT
    reason: Core function. Deep research extensively documents VEGF role in sprouting angiogenesis and directed endothelial migration.
    supported_by:
    - reference_id: PMID:20660291
      supporting_text: 2010 Jul 21. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
- term:
    id: GO:0002092
    label: positive regulation of receptor internalization
  evidence_type: IDA
  original_reference_id: PMID:20660291
  review:
    summary: VEGF binding induces VEGFR2 internalization as part of signaling.
    action: KEEP_AS_NON_CORE
    reason: Part of VEGFR2 signaling mechanism. Deep research notes neuropilin-1 guides VEGFR2 internalization and recycling.
    supported_by:
    - reference_id: PMID:20660291
      supporting_text: 2010 Jul 21. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
- term:
    id: GO:0043184
    label: vascular endothelial growth factor receptor 2 binding
  evidence_type: IPI
  original_reference_id: PMID:20660291
  review:
    summary: VEGFA binds VEGFR2 (KDR) to activate angiogenic signaling. Core molecular function.
    action: ACCEPT
    reason: Core molecular function. Deep research and multiple publications confirm VEGFA-VEGFR2 binding.
    supported_by:
    - reference_id: PMID:20660291
      supporting_text: gremlin binds VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IPI
  original_reference_id: PMID:20660291
  review:
    summary: VEGFA functions as a ligand for VEGFR1 and VEGFR2 receptors.
    action: ACCEPT
    reason: Core molecular function. VEGFA is the canonical ligand for VEGF receptors.
    supported_by:
    - reference_id: PMID:20660291
      supporting_text: 2010 Jul 21. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17082651
  review:
    summary: VEGFA is synthesized in cytoplasm before secretion. Deep research notes intracrine VEGF signaling.
    action: KEEP_AS_NON_CORE
    reason: Cellular component for synthesis. Primary functional location is extracellular but intracrine signaling also documented.
    supported_by:
    - reference_id: PMID:17082651
      supporting_text: Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.
- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IDA
  original_reference_id: PMID:17082651
  review:
    summary: VEGFA is stored in secretory granules before release.
    action: KEEP_AS_NON_CORE
    reason: Part of secretory pathway. Deep research notes VEGF trafficking through secretory pathway and plasma membrane localization.
    supported_by:
    - reference_id: PMID:17082651
      supporting_text: Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: IDA
  original_reference_id: PMID:21245381
  review:
    summary: VEGFA is a chemoattractant for endothelial cells and macrophages.
    action: ACCEPT
    reason: Core molecular function. Multiple independent IDA annotations confirm chemoattractant activity.
    supported_by:
    - reference_id: PMID:21245381
      supporting_text: Jan 18. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:20497126
  review:
    summary: VEGFA is the master regulator of angiogenesis. ISOFORM NOTE - applies to pro-angiogenic isoforms.
    action: ACCEPT
    reason: Core biological process. Consistent with other IDA evidence for this term.
    supported_by:
    - reference_id: PMID:20497126
      supporting_text: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:18059339
  review:
    summary: VEGF signaling activates transcription factors including those regulating gene expression.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect of VEGF signaling. VEGF activates ERK/MAPK which translocates to nucleus and activates transcription.
    supported_by:
    - reference_id: PMID:18059339
      supporting_text: Dec 3. The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis.
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: VEGFA has cytokine-like activity influencing immune cells via VEGFR1.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. VEGFA affects macrophage polarization but primary function is growth factor activity.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
- term:
    id: GO:0038091
    label: positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:17470632
  review:
    summary: VEGFA can cross-activate PDGFR signaling. Overly specific term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Overly specific/contorted term. VEGFA primarily signals through VEGFRs; PDGFR cross-talk is minor.
    supported_by:
    - reference_id: PMID:17470632
      supporting_text: Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: IDA
  original_reference_id: PMID:18440775
  review:
    summary: VEGFA is a chemoattractant. Duplicate annotation with different reference.
    action: ACCEPT
    reason: Core molecular function. Consistent with other chemoattractant annotations.
    supported_by:
    - reference_id: PMID:18440775
      supporting_text: 2008 Mar 18. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
- term:
    id: GO:0090050
    label: positive regulation of cell migration involved in sprouting angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:20551324
  review:
    summary: VEGFA promotes endothelial cell migration during sprouting angiogenesis.
    action: ACCEPT
    reason: Core function. Specific to sprouting angiogenesis, a key VEGFA-dependent process.
    supported_by:
    - reference_id: PMID:20551324
      supporting_text: 2010 Jun 15. Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Kruppel-like factor 4 (KLF4).
- term:
    id: GO:0030224
    label: monocyte differentiation
  evidence_type: IDA
  original_reference_id: PMID:21149635
  review:
    summary: VEGFA affects monocyte differentiation via VEGFR1 signaling.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. VEGFA affects immune cells but this is not a core function.
    supported_by:
    - reference_id: PMID:21149635
      supporting_text: 2010 Dec 13. Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions.
- term:
    id: GO:0030225
    label: macrophage differentiation
  evidence_type: IDA
  original_reference_id: PMID:21149635
  review:
    summary: VEGFA promotes M2 macrophage polarization via VEGFR1.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. Deep research documents VEGF promotion of M2 polarization but this is not core.
    supported_by:
    - reference_id: PMID:21149635
      supporting_text: 2010 Dec 13. Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions.
- term:
    id: GO:0005172
    label: vascular endothelial growth factor receptor binding
  evidence_type: IPI
  original_reference_id: PMID:10471394
  review:
    summary: VEGFA binds to VEGFR1 (Flt-1). Core molecular function.
    action: ACCEPT
    reason: Core molecular function. Multiple references confirm VEGFR binding.
    supported_by:
    - reference_id: PMID:10471394
      supporting_text: Characterization of the VEGF binding site on the Flt-1 receptor.
- term:
    id: GO:0005172
    label: vascular endothelial growth factor receptor binding
  evidence_type: IPI
  original_reference_id: PMID:11513746
  review:
    summary: VEGFA binds to VEGFRs. Duplicate with different reference.
    action: ACCEPT
    reason: Core molecular function. Additional reference supporting VEGFR binding.
    supported_by:
    - reference_id: PMID:11513746
      supporting_text: Direct identification of a major autophosphorylation site on vascular endothelial growth factor receptor Flt-1 that mediates phosphatidylinositol 3'-kinase binding.
- term:
    id: GO:0045785
    label: positive regulation of cell adhesion
  evidence_type: IDA
  original_reference_id: PMID:19674970
  review:
    summary: VEGFA promotes cell adhesion, supporting endothelial migration and vessel formation.
    action: KEEP_AS_NON_CORE
    reason: Supporting function for angiogenesis. Part of cell migration machinery.
    supported_by:
    - reference_id: PMID:19674970
      supporting_text: 2009 Aug 12. Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:12714610
  review:
    summary: VEGFA stimulates endothelial proliferation. Multiple independent references.
    action: ACCEPT
    reason: Core function. Consistent with other IDA annotations.
    supported_by:
    - reference_id: PMID:12714610
      supporting_text: Expression and localization of tenomodulin, a transmembrane type chondromodulin-I-related angiogenesis inhibitor, in mouse eyes.
- term:
    id: GO:0042056
    label: chemoattractant activity
  evidence_type: IDA
  original_reference_id: PMID:17082651
  review:
    summary: VEGFA is a chemoattractant. Additional independent reference.
    action: ACCEPT
    reason: Core molecular function. Consistent evidence across multiple publications.
    supported_by:
    - reference_id: PMID:17082651
      supporting_text: Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:10022831
  review:
    summary: VEGFA stimulates endothelial proliferation through VEGFR2.
    action: ACCEPT
    reason: Core function. Additional independent IDA evidence.
    supported_by:
    - reference_id: PMID:10022831
      supporting_text: Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.
- term:
    id: GO:0010595
    label: positive regulation of endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:10022831
  review:
    summary: VEGFA promotes endothelial cell migration through integrin-VEGFR2 cooperation.
    action: ACCEPT
    reason: Core function. The cited paper is about integrin alphavbeta3 and VEGFR2 activation.
    supported_by:
    - reference_id: PMID:10022831
      supporting_text: Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.
- term:
    id: GO:0043184
    label: vascular endothelial growth factor receptor 2 binding
  evidence_type: IPI
  original_reference_id: PMID:10022831
  review:
    summary: VEGFA binds VEGFR2/KDR. Paper about integrin-VEGFR2 activation.
    action: ACCEPT
    reason: Core molecular function. Multiple references confirm VEGFA-VEGFR2 binding.
    supported_by:
    - reference_id: PMID:10022831
      supporting_text: Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:18275976
  review:
    summary: VEGFA promotes angiogenesis. IMP evidence adds to existing support.
    action: ACCEPT
    reason: Core function. Multiple lines of evidence support this annotation.
    supported_by:
    - reference_id: PMID:18275976
      supporting_text: 2008 Jan 3. Aquaporin 1 is required for hypoxia-inducible angiogenesis in human retinal vascular endothelial cells.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IDA
  original_reference_id: PMID:10575000
  review:
    summary: VEGFA expression is induced by hypoxia and mediates cellular hypoxic response.
    action: KEEP_AS_NON_CORE
    reason: VEGFA is induced BY hypoxia rather than being a direct responder. This describes regulation of VEGFA rather than its function.
    supported_by:
    - reference_id: PMID:10575000
      supporting_text: Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:18577655
  review:
    summary: VEGFA stimulates endothelial proliferation. Additional IDA evidence.
    action: ACCEPT
    reason: Core function. Consistent with multiple other IDA annotations.
    supported_by:
    - reference_id: PMID:18577655
      supporting_text: The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:18577655
  review:
    summary: VEGFA is master regulator of angiogenesis. Additional IDA support.
    action: ACCEPT
    reason: Core function. Consistent evidence across publications.
    supported_by:
    - reference_id: PMID:18577655
      supporting_text: The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA stimulates endothelial proliferation. ISS from ortholog.
    action: ACCEPT
    reason: Core function. Supported by multiple IDA annotations for human.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:9202027
  review:
    summary: VEGFA stimulates endothelial proliferation. Additional IDA evidence.
    action: ACCEPT
    reason: Core function. Consistent with multiple other annotations.
    supported_by:
    - reference_id: PMID:9202027
      supporting_text: Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
- term:
    id: GO:0001968
    label: fibronectin binding
  evidence_type: IDA
  original_reference_id: PMID:14570917
  review:
    summary: VEGFA binds fibronectin in the extracellular matrix for storage/presentation.
    action: ACCEPT
    reason: Functional binding. Deep research notes VEGF binds ECM for storage and controlled release.
    supported_by:
    - reference_id: PMID:14570917
      supporting_text: '2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.'
- term:
    id: GO:0002687
    label: positive regulation of leukocyte migration
  evidence_type: TAS
  original_reference_id: PMID:1312256
  review:
    summary: VEGFA promotes leukocyte/monocyte migration through VEGFR1.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. VEGFA is chemoattractant for monocytes/macrophages but primary function is angiogenic.
    supported_by:
    - reference_id: PMID:1312256
      supporting_text: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA has cytokine-like functions affecting immune cells.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. VEGFA is primarily a growth factor; cytokine activity is secondary.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA is secreted and functions in extracellular space.
    action: ACCEPT
    reason: Core cellular component. VEGFA is a secreted growth factor acting extracellularly.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:9202027
  review:
    summary: VEGFA is secreted and detected in extracellular space.
    action: ACCEPT
    reason: Core cellular component. IDA evidence confirms extracellular localization.
    supported_by:
    - reference_id: PMID:9202027
      supporting_text: Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
- term:
    id: GO:0008083
    label: growth factor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: VEGFA is a canonical growth factor. ISS from ortholog.
    action: ACCEPT
    reason: Core molecular function. Supported by extensive IDA evidence.
- term:
    id: GO:0008083
    label: growth factor activity
  evidence_type: IDA
  original_reference_id: PMID:9202027
  review:
    summary: VEGFA is a canonical growth factor stimulating cell proliferation.
    action: ACCEPT
    reason: Core molecular function. Multiple IDA annotations confirm growth factor activity.
    supported_by:
    - reference_id: PMID:9202027
      supporting_text: Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IMP
  original_reference_id: PMID:14570917
  review:
    summary: VEGF isoforms differ in heparin binding affinity. VEGF165 has intermediate, VEGF189/206 high binding.
    action: ACCEPT
    reason: Core molecular function for ECM-binding isoforms. Deep research documents isoform-specific heparin binding.
    supported_by:
    - reference_id: PMID:14570917
      supporting_text: '2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.'
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:7929439
  review:
    summary: VEGFA stimulates cell proliferation through VEGFR2 signaling.
    action: ACCEPT
    reason: Core function. PMID:7929439 demonstrates mitogenic activity in KDR-expressing cells.
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
- term:
    id: GO:0008360
    label: regulation of cell shape
  evidence_type: IDA
  original_reference_id: PMID:10527820
  review:
    summary: VEGFA induces morphological changes in endothelial cells during migration.
    action: KEEP_AS_NON_CORE
    reason: Part of migration response. Cell shape changes support angiogenic cell migration.
    supported_by:
    - reference_id: PMID:10527820
      supporting_text: The effects of angiogenic growth factors on extravillous trophoblast invasion and motility.
- term:
    id: GO:0008360
    label: regulation of cell shape
  evidence_type: IDA
  original_reference_id: PMID:7929439
  review:
    summary: VEGFA induces striking morphological changes via VEGFR2/KDR.
    action: KEEP_AS_NON_CORE
    reason: Part of migration response. PMID:7929439 describes actin reorganization and membrane ruffling.
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IDA
  original_reference_id: PMID:7929439
  review:
    summary: VEGFA promotes cell migration/chemotaxis through VEGFR2/KDR.
    action: ACCEPT
    reason: Core function. PMID:7929439 demonstrates chemotaxis in KDR-expressing cells.
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
- term:
    id: GO:0043183
    label: vascular endothelial growth factor receptor 1 binding
  evidence_type: IPI
  original_reference_id: PMID:1312256
  review:
    summary: VEGFA binds VEGFR1/Flt-1 with high affinity but weak signaling.
    action: ACCEPT
    reason: Core molecular function. Deep research confirms VEGFA-VEGFR1 binding with Kd ~16 pM.
    supported_by:
    - reference_id: PMID:1312256
      supporting_text: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
- term:
    id: GO:0043184
    label: vascular endothelial growth factor receptor 2 binding
  evidence_type: IPI
  original_reference_id: PMID:1417831
  review:
    summary: VEGFA binds VEGFR2/KDR as the main pro-angiogenic receptor.
    action: ACCEPT
    reason: Core molecular function. VEGFR2 is the primary angiogenic signaling receptor.
    supported_by:
    - reference_id: PMID:1417831
      supporting_text: Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor.
- term:
    id: GO:0043536
    label: positive regulation of blood vessel endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:9202027
  review:
    summary: VEGFA promotes endothelial cell migration, essential for angiogenesis.
    action: ACCEPT
    reason: Core function. More specific than general cell migration term.
    supported_by:
    - reference_id: PMID:9202027
      supporting_text: Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
- term:
    id: GO:0050840
    label: extracellular matrix binding
  evidence_type: IC
  original_reference_id: PMID:14570917
  review:
    summary: VEGF binds ECM components including fibronectin and heparan sulfate proteoglycans.
    action: ACCEPT
    reason: Functional binding. Deep research documents ECM binding for VEGF storage and controlled release.
    supported_by:
    - reference_id: PMID:14570917
      supporting_text: '2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.'
- term:
    id: GO:0050927
    label: positive regulation of positive chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:12744932
  review:
    summary: VEGFA induces positive chemotaxis in trophoblast and endothelial cells.
    action: ACCEPT
    reason: Core function. VEGFA is a well-established chemoattractant.
    supported_by:
    - reference_id: PMID:12744932
      supporting_text: Vascular endothelial growth factor is a chemoattractant for trophoblast cells.
- term:
    id: GO:0050927
    label: positive regulation of positive chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:7929439
  review:
    summary: VEGFA induces chemotaxis through VEGFR2/KDR.
    action: ACCEPT
    reason: Core function. PMID:7929439 demonstrates chemotaxis in KDR-expressing cells.
    supported_by:
    - reference_id: PMID:7929439
      supporting_text: Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.
- term:
    id: GO:0005161
    label: platelet-derived growth factor receptor binding
  evidence_type: IPI
  original_reference_id: PMID:17470632
  review:
    summary: VEGFA may have some PDGFR cross-reactivity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Minor cross-talk. VEGFA primarily binds VEGFRs; PDGFR binding is not a core function.
    supported_by:
    - reference_id: PMID:17470632
      supporting_text: Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:17470632
  review:
    summary: VEGFA can localize to cell surface. Deep research notes plasma membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Part of secretory pathway. VEGFA is found on cell surface before release.
    supported_by:
    - reference_id: PMID:17470632
      supporting_text: Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IDA
  original_reference_id: PMID:17470632
  review:
    summary: VEGFA promotes cell migration. Additional independent reference.
    action: ACCEPT
    reason: Core function. Consistent with multiple other annotations.
    supported_by:
    - reference_id: PMID:17470632
      supporting_text: Apr 30. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IDA
  original_reference_id: PMID:16490744
  review:
    summary: VEGFA expression is induced by hypoxia via HIF-1. This annotation describes VEGFA regulation.
    action: KEEP_AS_NON_CORE
    reason: Describes regulation of VEGFA rather than VEGFA function. VEGFA is a hypoxia-responsive gene.
    supported_by:
    - reference_id: PMID:16490744
      supporting_text: 2006 Feb 20. Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:16490744
  review:
    summary: VEGFA is secreted into extracellular space.
    action: ACCEPT
    reason: Core cellular component. VEGFA functions as an extracellular signaling molecule.
    supported_by:
    - reference_id: PMID:16490744
      supporting_text: 2006 Feb 20. Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:11427521
  review:
    summary: VEGFA is essential for angiogenesis.
    action: ACCEPT
    reason: Core biological process. VEGFA is the master regulator of angiogenesis.
    supported_by:
    - reference_id: PMID:11427521
      supporting_text: Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor.
- term:
    id: GO:0001570
    label: vasculogenesis
  evidence_type: TAS
  original_reference_id: PMID:15015550
  review:
    summary: VEGFA is essential for de novo blood vessel formation from vascular progenitors.
    action: ACCEPT
    reason: Core biological process. Deep research documents VEGF role in vasculogenesis.
    supported_by:
    - reference_id: PMID:15015550
      supporting_text: Vasculogenesis and angiogenesis.
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: TAS
  original_reference_id: PMID:15351965
  review:
    summary: VEGFA has neurotrophic/neuroprotective effects beyond angiogenesis.
    action: KEEP_AS_NON_CORE
    reason: Secondary function. VEGFA affects neural development but primary function is angiogenic.
    supported_by:
    - reference_id: PMID:15351965
      supporting_text: 'VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection.'
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IDA
  original_reference_id: PMID:15001987
  review:
    summary: VEGF binds heparin. Isoform-specific binding affinity.
    action: ACCEPT
    reason: Core molecular function. Multiple independent references confirm heparin binding.
    supported_by:
    - reference_id: PMID:15001987
      supporting_text: Heparin affin regulatory peptide binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: NAS
  original_reference_id: PMID:14570917
  review:
    summary: VEGF localizes to extracellular matrix especially longer isoforms.
    action: ACCEPT
    reason: Functional localization. VEGF189/206 are matrix-bound; matrix serves as VEGF reservoir.
    supported_by:
    - reference_id: PMID:14570917
      supporting_text: '2003 Oct 21. pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.'
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:10066377
  review:
    summary: VEGFA promotes endothelial cell survival through PI3K-Akt pathway.
    action: ACCEPT
    reason: Core function for endothelial cell survival. Deep research documents Akt-mediated anti-apoptotic signaling.
    supported_by:
    - reference_id: PMID:10066377
      supporting_text: VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling.
- term:
    id: GO:0050930
    label: induction of positive chemotaxis
  evidence_type: NAS
  original_reference_id: PMID:12744932
  review:
    summary: NAS evidence for chemotaxis. Consistent with IBA and other evidence.
    action: ACCEPT
    reason: Core biological process. VEGFA induces chemotaxis in multiple cell types.
    supported_by:
    - reference_id: PMID:12744932
      supporting_text: Vascular endothelial growth factor is a chemoattractant for trophoblast cells.
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: file:human/VEGFA/VEGFA-deep-research-perplexity.md
  review:
    summary: 'CRITICAL: The VEGF165B isoform (P15692-8) is ANTI-ANGIOGENIC. It binds VEGFR2 but fails to activate downstream signaling, acting as an endogenous inhibitor of angiogenesis. VEGF165B inhibits VEGF165-induced proliferation, migration, and vasodilatation. In colon carcinoma, VEGF165B inhibits tumor growth by blocking angiogenesis. This function is NOT captured by any existing GOA annotation.'
    action: NEW
    reason: Critical missing annotation. VEGF165B has opposite biological activity to other isoforms. The deep research documents that VEGF165B has anti-angiogenic properties and inhibits tumor growth. This represents a fundamentally different function from the pro-angiogenic isoforms currently annotated.
    additional_reference_ids:
    - file:human/VEGFA/VEGFA-deep-research-perplexity.md
core_functions:
- molecular_function:
    id: GO:0005172
    label: vascular endothelial growth factor receptor binding
  description: VEGFA binds to VEGFR1 (FLT1), VEGFR2 (KDR), and co-receptors including neuropilins. This is the primary molecular function enabling all downstream signaling. All isoforms bind receptors, though VEGF165B binding does not activate signaling.
  directly_involved_in:
  - id: GO:0048010
    label: vascular endothelial growth factor receptor signaling pathway
  - id: GO:0045766
    label: positive regulation of angiogenesis
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:7929439
    supporting_text: Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR.
- molecular_function:
    id: GO:0008083
    label: growth factor activity
  description: 'VEGFA is a canonical growth factor stimulating endothelial cell proliferation through VEGFR2-PLCgamma-PKC-MAPK signaling. ISOFORM NOTE: Pro-angiogenic isoforms only; VEGF165B lacks mitogenic activity.'
  directly_involved_in:
  - id: GO:0008284
    label: positive regulation of cell population proliferation
  - id: GO:0001525
    label: angiogenesis
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:21771332
    supporting_text: 50 ng/mL VEGF stimulated HUVEC proliferation by 27% relative to untreated cells.
- molecular_function:
    id: GO:0042056
    label: chemoattractant activity
  description: VEGFA is a chemoattractant for endothelial cells (directing sprouting angiogenesis) and for monocytes/macrophages (via VEGFR1). Essential for guided vessel growth and inflammatory cell recruitment.
  directly_involved_in:
  - id: GO:0001525
    label: angiogenesis
  - id: GO:0030335
    label: positive regulation of cell migration
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:7929439
    supporting_text: The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/VEGFA/VEGFA-deep-research-perplexity.md
  title: Deep research summary for VEGFA from Perplexity
  findings: []
- id: PMID:10022831
  title: Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.
  findings: []
- id: PMID:10066377
  title: VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling.
  findings: []
- id: PMID:10471394
  title: Characterization of the VEGF binding site on the Flt-1 receptor.
  findings: []
- id: PMID:10527820
  title: The effects of angiogenic growth factors on extravillous trophoblast invasion and motility.
  findings: []
- id: PMID:10543948
  title: 'Solution structure of the VEGF-binding domain of Flt-1: comparison of its free and bound states.'
  findings: []
- id: PMID:10575000
  title: Placenta growth factor and vascular endothelial growth factor B and C expression in microvascular endothelial cells and pericytes. Implication in autocrine and paracrine regulation of angiogenesis.
  findings: []
- id: PMID:11427521
  title: Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor.
  findings: []
- id: PMID:11461089
  title: Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells.
  findings: []
- id: PMID:11513746
  title: Direct identification of a major autophosphorylation site on vascular endothelial growth factor receptor Flt-1 that mediates phosphatidylinositol 3'-kinase binding.
  findings: []
- id: PMID:12207021
  title: The cystine knot promotes folding and not thermodynamic stability in vascular endothelial growth factor.
  findings: []
- id: PMID:12714610
  title: Expression and localization of tenomodulin, a transmembrane type chondromodulin-I-related angiogenesis inhibitor, in mouse eyes.
  findings: []
- id: PMID:12744932
  title: Vascular endothelial growth factor is a chemoattractant for trophoblast cells.
  findings: []
- id: PMID:1312256
  title: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.
  findings: []
- id: PMID:1417831
  title: Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor.
  findings: []
- id: PMID:14570917
  title: 'pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release.'
  findings: []
- id: PMID:15001987
  title: Heparin affin regulatory peptide binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis.
  findings: []
- id: PMID:15015550
  title: Vasculogenesis and angiogenesis.
  findings: []
- id: PMID:15351965
  title: 'VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection.'
  findings: []
- id: PMID:16150726
  title: Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner.
  findings: []
- id: PMID:16489009
  title: Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein.
  findings: []
- id: PMID:16490744
  title: Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.
  findings: []
- id: PMID:16763549
  title: Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.
  findings: []
- id: PMID:17082651
  title: Expression and functions of the vascular endothelial growth factors and their receptors in human basophils.
  findings: []
- id: PMID:17222790
  title: Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth.
  findings: []
- id: PMID:17446437
  title: 'Association of ATP1A1 and dear single-nucleotide polymorphism haplotypes with essential hypertension: sex-specific and haplotype-specific effects.'
  findings: []
- id: PMID:17470632
  title: Vascular endothelial growth factor can signal through platelet-derived growth factor receptors.
  findings: []
- id: PMID:18059339
  title: The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis.
  findings: []
- id: PMID:18093989
  title: Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling.
  findings: []
- id: PMID:18275976
  title: Aquaporin 1 is required for hypoxia-inducible angiogenesis in human retinal vascular endothelial cells.
  findings: []
- id: PMID:18440775
  title: Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase.
  findings: []
- id: PMID:18577655
  title: The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells.
  findings: []
- id: PMID:19033661
  title: AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice.
  findings: []
- id: PMID:19148554
  title: Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2.
  findings: []
- id: PMID:19652095
  title: Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor.
  findings: []
- id: PMID:19674970
  title: Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells.
  findings: []
- id: PMID:20048167
  title: Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers.
  findings: []
- id: PMID:20123964
  title: Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
  findings: []
- id: PMID:20497126
  title: Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.
  findings: []
- id: PMID:20551324
  title: Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Kruppel-like factor 4 (KLF4).
  findings: []
- id: PMID:20660291
  title: Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2.
  findings: []
- id: PMID:21149635
  title: Monocytic cells derived from human embryonic stem cells and fetal liver share common differentiation pathways and homeostatic functions.
  findings: []
- id: PMID:21245381
  title: Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells.
  findings: []
- id: PMID:21653826
  title: VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation.
  findings: []
- id: PMID:21771332
  title: 'Glioblastoma-derived leptin induces tube formation and growth of endothelial cells: comparison with VEGF effects.'
  findings: []
- id: PMID:22020326
  title: MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway.
  findings: []
- id: PMID:23083510
  title: miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia.
  findings: []
- id: PMID:23374253
  title: Endorepellin laminin-like globular 1/2 domains bind Ig3-5 of vascular endothelial growth factor (VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells.
  findings: []
- id: PMID:23583373
  title: Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity.
  findings: []
- id: PMID:23688497
  title: MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2.
  findings: []
- id: PMID:23878390
  title: MicroRNA 329 suppresses angiogenesis by targeting CD146.
  findings: []
- id: PMID:24844779
  title: Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3.
  findings: []
- id: PMID:24865854
  title: Dysregulated miR-361-5p/VEGF axis in the plasma and endothelial progenitor cells of patients with coronary artery disease.
  findings: []
- id: PMID:25132001
  title: Development of a highly-potent anti-angiogenic VEGF8-109 heterodimer by directed blocking of its VEGFR-2 binding site.
  findings: []
- id: PMID:25251394
  title: MicroRNA-377 regulates mesenchymal stem cell-induced angiogenesis in ischemic hearts by targeting VEGF.
  findings: []
- id: PMID:25825981
  title: EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.
  findings: []
- id: PMID:26268439
  title: p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.
  findings: []
- id: PMID:26299712
  title: High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.
  findings: []
- id: PMID:26598555
  title: VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.
  findings: []
- id: PMID:26683794
  title: Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes.
  findings: []
- id: PMID:28977001
  title: MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2.
  findings: []
- id: PMID:30106099
  title: Overexpression of miR‑21 is involved in acute monocytic leukemia‑associated angiogenesis by targeting IL‑12.
  findings: []
- id: PMID:31915155
  title: PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:7929439
  title: Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.
  findings: []
- id: PMID:9202027
  title: Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion.
  findings: []
- id: PMID:9393862
  title: Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.
  findings: []
- id: Reactome:R-HSA-1235037
  title: Expression of VEGFA
  findings: []
- id: Reactome:R-HSA-194310
  title: VEGF-A,C,D bind to VEGFR2 leading to receptor dimerization
  findings: []
- id: Reactome:R-HSA-194311
  title: VEGFA,B,PLGF bind to VEGFR1 leading to receptor dimerization
  findings: []
- id: Reactome:R-HSA-195378
  title: Homodimerization of VEGF proteins
  findings: []
- id: Reactome:R-HSA-4420083
  title: PTK2 binds p-S-SHB and is recruited to p-6Y-VEGFR2
  findings: []
- id: Reactome:R-HSA-4420099
  title: 'p-6Y-VEGFR2 binds SHB '
  findings: []
- id: Reactome:R-HSA-4420107
  title: p-6Y-VEGFR2 binds SHC-transforming protein 2
  findings: []
- id: Reactome:R-HSA-4420117
  title: VEGFR2 autophosphorylates
  findings: []
- id: Reactome:R-HSA-4420121
  title: SFKs phosphorylate PLCG1
  findings: []
- id: Reactome:R-HSA-4420128
  title: SRC-1 phosphorylates SHB
  findings: []
- id: Reactome:R-HSA-4420140
  title: SRC1-1 binds SH2D2A and is recruited to VEGFR2
  findings: []
- id: Reactome:R-HSA-4420143
  title: p-6Y-VEGFR2 binds SH2D2A
  findings: []
- id: Reactome:R-HSA-4420153
  title: p-6Y-VEGFR2 binds PLCG1
  findings: []
- id: Reactome:R-HSA-4420202
  title: PLCG1 disassociates from VEGFR2 and translocate to PM
  findings: []
- id: Reactome:R-HSA-4420206
  title: Phosphorylation of SRC-1
  findings: []
- id: Reactome:R-HSA-481007
  title: Exocytosis of platelet alpha granule contents
  findings: []
- id: Reactome:R-HSA-5218640
  title: SRC-1 phosphorylates p-Y397-PTK2
  findings: []
- id: Reactome:R-HSA-5218642
  title: PTK2 autophosphorylates
  findings: []
- id: Reactome:R-HSA-5218643
  title: HSP90AA1 binds p-6Y-VEGFR2
  findings: []
- id: Reactome:R-HSA-5218645
  title: SRC-1 binds p-Y397-PTK2
  findings: []
- id: Reactome:R-HSA-5218804
  title: p38 MAPK activation by VEGFR
  findings: []
- id: Reactome:R-HSA-5218806
  title: FYN autophosphorylates
  findings: []
- id: Reactome:R-HSA-5218809
  title: PTK2 and SRC-1 phosphorylate PXN on Y31 and Y118
  findings: []
- id: Reactome:R-HSA-5218811
  title: DOCK180:ELMO binds CRK
  findings: []
- id: Reactome:R-HSA-5218812
  title: FYN phosphorylates PAK2
  findings: []
- id: Reactome:R-HSA-5218814
  title: PAK2 autophorylates
  findings: []
- id: Reactome:R-HSA-5218815
  title: p-6Y-VEGFR2 binds NCK
  findings: []
- id: Reactome:R-HSA-5218818
  title: Integrin alphaVbeta3 binds p-6Y-VEGFR2
  findings: []
- id: Reactome:R-HSA-5218819
  title: VEGFA dimer:p-6Y-VEGFR2 dimer:PI3K phosphorylates PIP2 to PIP3
  findings: []
- id: Reactome:R-HSA-5218820
  title: Src kinases phosphorylate VAV
  findings: []
- id: Reactome:R-HSA-5218822
  title: CRK binds BCAR1 and or PXN
  findings: []
- id: Reactome:R-HSA-5218824
  title: p-6Y-VEGFR2 binds FYN
  findings: []
- id: Reactome:R-HSA-5218826
  title: Active ROCK1,ROCK2 phosphorylates p-5Y-PTK2 on S732
  findings: []
- id: Reactome:R-HSA-5218830
  title: SRC-1 phosphorylates PTK2-beta
  findings: []
- id: Reactome:R-HSA-5218832
  title: CDC42:GTP binds PAK2
  findings: []
- id: Reactome:R-HSA-5218836
  title: PTK2beta binds alphaVbeta3
  findings: []
- id: Reactome:R-HSA-5218838
  title: PXN binds p-6Y,S732-PTK2
  findings: []
- id: Reactome:R-HSA-5218839
  title: DOCK180:ELMO exchanges GTP for GDP, activating RAC1
  findings: []
- id: Reactome:R-HSA-5218847
  title: PAK2 binds NCK
  findings: []
- id: Reactome:R-HSA-5218851
  title: p-Y402-PTK2B phosphorylates p-5Y,S732-PTK2 on Y407
  findings: []
- id: Reactome:R-HSA-5218854
  title: p-Y420-FYN is phosphorylated on S21
  findings: []
- id: Reactome:R-HSA-5357429
  title: AXL autophosphorylates on Y779 and Y821
  findings: []
- id: Reactome:R-HSA-5357432
  title: AXL binds SRC-1
  findings: []
- id: Reactome:R-HSA-5357479
  title: p-AXL binds PI3K
  findings: []
- id: Reactome:R-HSA-6789615
  title: Expression of STAT3-upregulated extracellular proteins
  findings: []
- id: Reactome:R-HSA-8864936
  title: VEGFA gene expression is inhibited by the TFAP2A homodimer
  findings: []
- id: Reactome:R-HSA-9679477
  title: VEGFA-165 dimer binds VEGFA inhibitors
  findings: []
- id: Reactome:R-HSA-9691215
  title: VEGFA-165 dimer binds VEGFR2 dimer
  findings: []
alternative_products:
- name: L-VEGF189
  id: P15692-13
  description: >-
    Long form with extended N-terminus. Has intracellular functions in addition
    to secreted
    VEGF activities. The L-VEGF forms may have distinct nuclear/intracellular signaling
    roles.
- name: VEGF206
  id: P15692-1
  sequence_note: VSP_061891, VSP_061898
  description: >-
    The longest secreted isoform (206 AA). Strongly heparin-binding and matrix-bound.
    Produces dense, localized vascular sprouting patterns. Less diffusible than
    shorter isoforms.
- name: VEGF189
  id: P15692-2
  sequence_note: VSP_061891
  description: >-
    A strongly heparin-binding, matrix-bound isoform (189 AA). Sequestered in extracellular
    matrix and released by proteases. Produces localized angiogenic effects. Important
    for
    establishing vascular patterning gradients.
- name: VEGF183
  id: P15692-3
  sequence_note: VSP_061891, VSP_061897
  description: >-
    An intermediate heparin-binding isoform. Properties intermediate between VEGF165
    and
    VEGF189.
- name: VEGF165 (VEGF)
  id: P15692-4
  sequence_note: VSP_061891, VSP_061894
  description: >-
    The predominant and best-characterized isoform (165 AA). Intermediate heparin
    binding
    and diffusibility. Binds both VEGFR1/VEGFR2 and neuropilin-1 (NRP1) coreceptor.
    This is
    the canonical pro-angiogenic isoform that most GO annotations refer to. Target
    of
    anti-VEGF therapies (bevacizumab).
- name: VEGF148
  id: P15692-5
  sequence_note: VSP_061891, VSP_061894, VSP_061901,
  description: >-
    A less common isoform with intermediate properties. Functional role less well
    characterized
    than VEGF165.
- name: VEGF145
  id: P15692-6
  sequence_note: VSP_061891, VSP_061899, VSP_061900
  description: >-
    An isoform with heparin-binding properties. Binds VEGFR2 but not neuropilins.
    Found in
    reproductive tissues and some tumors.
- name: VEGF165B
  id: P15692-8
  sequence_note: VSP_061891, VSP_061894, VSP_061903
  description: >-
    CRITICAL: An ANTI-angiogenic isoform! Uses distal splice site in exon 8 (exon
    8b) producing
    an alternative C-terminus. Binds VEGFR2 but does NOT activate downstream signaling
    for
    angiogenesis. Acts as endogenous inhibitor of pro-angiogenic VEGF isoforms.
    Downregulated
    in cancer, upregulated in quiescent vasculature. GO annotations for "positive
    regulation
    of angiogenesis" do NOT apply to this isoform - it has the OPPOSITE function.
- name: VEGF121
  id: P15692-9
  sequence_note: VSP_061891, VSP_061895, VSP_061896
  description: >-
    The shortest secreted isoform (121 AA). Freely diffusible, lacks heparin-binding
    domain.
    Does not bind neuropilins. Produces diffuse vascular networks. Important for
    long-range
    angiogenic signaling.
- name: VEGF111
  id: P15692-10
  sequence_note: VSP_061891, VSP_061892, VSP_061893
  description: >-
    A short isoform generated by alternative splicing. Less well characterized than
    VEGF121
    and VEGF165.
- name: L-VEGF165
  id: P15692-11
  sequence_note: VSP_061894
  description: >-
    Long form of VEGF165 with extended N-terminus. May have intracellular functions
    in
    addition to secreted activities.
- name: L-VEGF121
  id: P15692-12
  sequence_note: VSP_061895, VSP_061896
  description: >-
    Long form of VEGF121 with extended N-terminus. May have intracellular functions.
- name: L-VEGF206
  id: P15692-14
  sequence_note: VSP_061898
  description: >-
    Long form of VEGF206 with extended N-terminus. May have intracellular functions.
- name: '15'
  id: P15692-15
  sequence_note: VSP_061894, VSP_061903
  description: >-
    A less characterized isoform. May have anti-angiogenic properties based on exon
    8b usage.
- name: '16'
  id: P15692-16
  sequence_note: VSP_061897
  description: >-
    A less characterized isoform. Functional role not well established.
- name: '17'
  id: P15692-17
  sequence_note: VSP_061894, VSP_061901, VSP_061902
  description: >-
    A less characterized isoform. Functional role not well established.
- name: '18'
  id: P15692-18
  sequence_note: VSP_061892, VSP_061893
  description: >-
    A less characterized isoform. Functional role not well established.

VEGFA

Gene Description

Existing Annotations Review

Core Functions

VEGFA binds to VEGFR1 (FLT1), VEGFR2 (KDR), and co-receptors including neuropilins. This is the primary molecular function enabling all downstream signaling. All isoforms bind receptors, though VEGF165B binding does not activate signaling.

VEGFA is a canonical growth factor stimulating endothelial cell proliferation through VEGFR2-PLCgamma-PKC-MAPK signaling. ISOFORM NOTE: Pro-angiogenic isoforms only; VEGF165B lacks mitogenic activity.

VEGFA is a chemoattractant for endothelial cells (directing sprouting angiogenesis) and for monocytes/macrophages (via VEGFR1). Essential for guided vessel growth and inflammatory cell recruitment.

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Perplexity

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Comprehensive Functional Annotation of VEGFA (Vascular Endothelial Growth Factor A)

Gene Structure and Chromosomal Organization

Protein Structure and Cystine-Knot Motif

Alternative Splicing and Isoform Diversity

VEGF Receptor Structure and Binding Interactions

VEGFR2 Signaling Pathways and Downstream Effectors

Biological Functions in Angiogenesis and Vasculogenesis

VEGF Secretion, Trafficking, and Subcellular Localization

Regulation of VEGF Expression

VEGF in Wound Healing and Tissue Regeneration

Pathological VEGF Signaling in Cancer

VEGF in Regulation of Vascular Permeability and Leukocyte Infiltration

VEGF Signaling in Immune Cell Modulation

VEGF in Developmental Organogenesis

Conclusion

Citations

Notes

VEGFA Notes - ISOFORMS Project

Key Isoform Biology

Major Isoforms by Length

Critical Isoform Difference: VEGF165 vs VEGF165B

Heparin Binding and Matrix Association

GOA Annotation Status

Expected Annotation Issues

Key References

Bioreason Rl Review

BioReason-Pro RL Review: VEGFA (human)

Functional Summary Review

Notes on thinking trace

📄 View Raw YAML