Vegfa (rat, UniProt P16612) - manual literature synthesis

No deep-research API was available for this review. This file is a manual synthesis
written by the reviewer from the cached publications in publications/, the rat and
human UniProt records, and the existing human VEGFA review
(genes/human/VEGFA/VEGFA-ai-review.yaml). Every assertion carries its source.

Identity and structure

• Rat Vegfa (RGD:619991, GeneID 83785) encodes vascular endothelial growth factor A, a
  secreted, disulfide-linked homodimeric cystine-knot growth factor of the PDGF/VEGF
  family. UniProt: "Belongs to the PDGF/VEGF growth factor family." and
  "Homodimer; disulfide-linked (PubMed:7706320)." [file:rat/Vegfa/Vegfa-uniprot.txt]
• The rat protein was first purified from glioma cells: "Glioma-derived vascular
  endothelial cell growth factor (GD-VEGF) is a 46-kDa dimeric glycoprotein mitogen"
  and "The GD-VEGF homodimeric subunit is homologous to the platelet-derived growth
  factor A and B chains" PMID:2320579.
• Alternative splicing yields VEGF-A188 (displayed), VEGF-A164, VEGF-A144 and VEGF-A120.
  Isoforms differ in their basic heparin/ECM-binding exons: "VEGF-A120 is acidic and
  freely secreted." while "VEGF-A188 is very basic, it is cell-associated after secretion
  and is bound avidly by heparin and the extracellular matrix"
  [file:rat/Vegfa/Vegfa-uniprot.txt]. In rat uterus "The VEG/PF gene is alternatively
  spliced and gives rise to three transcripts coding for proteins of 188, 164, and 120
  amino acids" PMID:8344219.

Molecular function

• Receptor ligand for the receptor tyrosine kinases VEGFR1/FLT1 and VEGFR2/KDR and for the
  co-receptor NRP1. UniProt: "Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan
  sulfate and heparin." [file:rat/Vegfa/Vegfa-uniprot.txt]. Human/porcine-cell work:
  "Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which
  binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR."
  PMID:7929439; KDR "encodes a receptor for VEGF" PMID:1417831; "flt encodes a
  receptor for VEGF-VPF" PMID:1312256; NRP1 "binds vascular endothelial growth factor
  (VEGF)-A and is thought to act as a coreceptor" for KDR PMID:21653826.
• Signalling through VEGFR2 drives chemotaxis and mitogenesis: "The KDR expressing cells
  showed striking changes in cell morphology, actin reorganization and membrane ruffling,
  chemotaxis and mitogenicity upon VEGF stimulation" PMID:7929439.
• Rat in vitro evidence that VEGF acts through VEGFR2 on neural precursors: "the effect
  of VEGF was blocked by the VEGFR2/Flk-1 receptor tyrosine kinase inhibitor SU1498"
  [PMID:12181492, full text].
• Heparin/ECM: fibronectin binding is pH regulated PMID:14570917; rat glomerular
  VEGF localizes "to podocytes and in the basement membrane" PMID:11940521.
• Secondary ligand activity for PDGF receptors: "VEGF-A binds to both PDGFRalpha and
  PDGFRbeta and induces tyrosine phosphorylation" in mesenchymal stem cells
  PMID:17470632.
• Binding by the heparin-binding growth factor pleiotrophin (HARP) sequesters VEGF from
  VEGFR2 in rat C6 glioma cells PMID:17881084.

Biological processes (rat experimental evidence)

• Angiogenesis and alveolarization: "VEGF blockade decreases lung VEGF and VEGF receptor 2
  (VEGFR-2) expression in newborn rats and impairs alveolar development" PMID:16230500.
• Coronary collateral growth requires VEGF PMID:16203926; postnatal coronary
  angiogenesis [PMID:11397779, abstract not cached].
• Ischaemic hindlimb angiogenesis promoted by VEGFA-transduced EPCs PMID:23562340.
• Vascular permeability: soluble VEGFR2 "prevented I/R-mediated increase in lung vascular
  permeability in rats" PMID:16793871; VEGF increases glomerular endothelial
  permeability PMID:16160062 and caveolae/fenestrae formation PMID:11940521.
• Neurogenesis and neuroprotection: VEGF stimulates BrdU incorporation into neuronal
  precursors in vitro and in vivo PMID:12181492; hippocampal VEGF gene transfer
  increases neurogenesis in adult rats PMID:15258583; VEGF-A reduces retinal neuron
  apoptosis PMID:17591953; endogenous VEGF protects astrocytes during
  oxygen-glucose deprivation PMID:18614764.
• Autocrine/paracrine mitogen for vascular smooth muscle cells downstream of MCP-1
  PMID:14693680.
• Exercise-induced bone angiogenesis and bone gain depend on VEGF PMID:15312247.
• VEGF secreted by activated T cells promotes a Th1 phenotype PMID:15034080.

Expression and regulation (IEP-type evidence)

• Hypoxia induces VEGF in cardiomyocytes; hypoxic myocyte medium induces endothelial
  COX-2 through VEGF PMID:12881220.
• Estrogen rapidly induces uterine VEGF PMID:8344219 through PI3K-dependent recruitment
  of ERalpha and HIF-1alpha to the promoter PMID:17272396.
• Dexamethasone represses VEGF in glioma cells PMID:10215998 and placenta
  PMID:16959835; FGF-2 induces VEGF-A via ATF-4 in smooth muscle cells PMID:18617696;
  mechanical load induces VEGF mRNA in neonatal cardiomyocytes [PMID:19012730, full
  text]; doxorubicin increases VEGF-A release from cardiac endothelial cells
  PMID:22326847; diesel exhaust lowers cardiac VEGF [PMID:23887904, full text]; a
  hyaluronan-butyrate-retinoate ester increases VEGF transcription and secretion in rat
  cardiomyocytes and Stro-1 cells: "The HBR treatment enhanced the secretion of VEGF and
  HGF in the culture medium from both RCm and Stro-1 cells." [PMID:20097747, full text].
• Expression in mammary gland increases during pregnancy and lactation [PMID:10878616 via
  UniProt].

Interpretation for GO review

The core, conserved function is that of an extracellular receptor ligand (growth factor)
for VEGFR1/VEGFR2 (with NRP1 and heparan sulfate as co-receptors) that drives endothelial
proliferation, migration/chemotaxis, survival and permeability, and thereby angiogenesis.
Many GOA rows are developmental phenotypes transferred from mouse knockouts, or
expression-response (IEP) rows, which are non-core. Transcription, mRNA-stability and
gene-expression rows reflect distal signalling outputs, not activities of VEGF-A itself.