| Entity | How generated | Localization / bioavailability | Main receptors / co-receptors and pathway notes | Clinical relevance / examples | Key evidence citations |
|---|---|---|---|---|---|
| VEGF121 | Alternative splicing of the 8-exon human VEGFA gene | Freely diffusible; little/no heparan-sulfate proteoglycan (HSPG) sequestration compared with longer isoforms | VEGFA ligand for VEGFR1 and VEGFR2; signalling is dominated functionally by VEGFR2, which activates PLCγ-PKC-ERK, PI3K-AKT, and FAK programs controlling endothelial proliferation, migration, survival, and permeability; neuropilins can act as co-receptors for VEGFA isoforms | Core VEGFA biology underpinning anti-VEGF therapies used in oncology and neovascular eye disease | (pqac-00000000, pqac-00000006) |
| VEGF165 | Alternative splicing; canonical major pro-angiogenic isoform | Partly diffusible and partly HSPG/ECM-bound via exon 7-encoded heparin-binding features | Binds VEGFR1/VEGFR2 and can engage neuropilin co-receptors; often treated as the classic pro-angiogenic VEGFA subtype; VEGFR2 is the main pro-angiogenic signalling receptor, whereas VEGFR1 can limit VEGFA available to VEGFR2 | Central target context for ocular anti-VEGF therapy; VEGF/VEGFR2 axis is a main driver of retinal/fundus neovascularization and vision-preserving anti-VEGF treatment | (pqac-00000000, pqac-00000001, pqac-00000006) |
| VEGF189 / VEGF206 | Alternative splicing including longer C-terminal heparin-binding regions (exons 6/7 contributions) | Largely sequestered in extracellular matrix and on HSPGs; relatively less diffusible than VEGF121/165 | Same VEGFA receptor system, but ECM retention alters spatial signalling gradients and vascular patterning/bioavailability | Relevant to tissue patterning and local VEGFA availability; illustrates why different VEGFA forms may respond differently to release/proteolysis in disease tissues | (pqac-00000000, pqac-00000006) |
| VEGFxxxb / VEGF165b | Alternative splice variants with altered terminal sequence; reported inhibitory variants remain debated | Secreted isoform class; not primarily defined by ECM retention in the cited evidence | Can bind VEGFR2 but are now viewed in authoritative review as weak agonists rather than true antagonists; existence/physiological role of endogenous anti-angiogenic VEGFxxxb remains debated | Important for interpretation of isoform-specific therapeutic strategies, but not established as a straightforward endogenous anti-VEGF system | (pqac-00000002, pqac-00000007) |
| VEGF110 / VEGF113 fragments | Proteolytic processing of VEGFA isoforms into shorter bioactive fragments | Shorter bioactive forms with altered bioavailability relative to parent isoforms | Retain VEGF bioactivity within the VEGFR pathway; proteolysis is part of how VEGFA availability and vascular patterning are tuned | Shows that VEGFA function is controlled not only by splicing but also by extracellular processing; relevant to diseased matrix remodeling | (pqac-00000002, pqac-00000006) |
| L-VEGF | Non-canonical translation from an upstream CUG start codon under hypoxic conditions, producing a longer VEGF-A isoform with an N-terminal extension | Intracellular precursor form before cleavage; produced under hypoxia | Proteolytically cleaved upstream of the canonical VEGF start to yield secreted VEGF-A plus N-VEGF; supports a dual response in which one product acts extracellularly and the other intracellularly/nuclearly | Expands VEGFA functional annotation beyond secreted angiogenic ligand biology; relevant to hypoxia adaptation and possibly cancer/ischemic biology | (pqac-00000008, pqac-00000009) |
| N-VEGF | N-terminal fragment generated by proteolytic cleavage of L-VEGF | Retained intracellularly and mobilized to the nucleus; forced nuclear localization is sufficient to induce part of a hypoxia-like program even in normoxia | Does not function as the classic extracellular VEGFR ligand; instead acts as a nuclear/autoregulatory arm of VEGF-A, inducing genes including Hif1α and VEGF-A isoforms and supporting anti-apoptotic/hypoxia-survival programs; deletion increases hypoxia-related apoptosis | Important nuance for UniProt P15692 because the reviewed long-form precursor contains both secreted VEGFA and N-VEGF products; suggests VEGFA biology includes intracrine nuclear stress-response functions in addition to paracrine angiogenesis | (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000011) |
| Secreted VEGFA signalling axis (cross-isoform summary) | Combined output of VEGFA splicing, translation, and processing | Secreted into extracellular space, with isoform-dependent diffusibility vs ECM sequestration | VEGFR2 is the principal pro-angiogenic receptor; VEGFR1 has weaker signalling and important decoy/regulatory behavior; co-receptors NRP1/NRP2 enhance signalling context; downstream pathways include PLCγ-PKC-ERK, PI3K-AKT, and FAK | Foundation of approved anti-VEGF/anti-VEGFR treatment classes in oncology and ophthalmology; anti-VEGF therapy markedly improved outcomes in neovascular eye disease, though repeated injections and incomplete response remain limitations | (pqac-00000000, pqac-00000001, pqac-00000003) |
| Clinical translation: anti-VEGF drugs and gene therapy | Therapeutic blockade of VEGFA or VEGF-pathway signalling; emerging vectored anti-VEGF expression approaches | Drug delivery is systemic or intraocular depending on indication; ocular therapy is typically intravitreal, while gene therapy aims longer intraocular durability | Therapeutics target the VEGF pathway rather than one single endogenous isoform; review evidence notes approvals across ophthalmology/oncology and emerging gene-therapy approaches for nAMD such as RGX-314 in early clinical development | Real-world and trial context: anti-VEGF transformed neovascular eye disease care; recent cited review context notes RGX-314 phase 1/2a development and long-term outcomes analyses, highlighting current movement toward more durable VEGF-pathway suppression | (pqac-00000003, pqac-00000004, pqac-00000006) |


*Table: This table summarizes the main functional VEGFA products relevant to human UniProt P15692, including splice isoforms, proteolytic fragments, and the long-form L-VEGF/N-VEGF pathway. It also links these molecular forms to receptor signaling and current clinical translation in ophthalmology and oncology.*