VEGFA Gene Function
Vascular Endothelial Growth Factor A
Overview
VEGFA is the principal mediator of angiogenesis, stimulating endothelial cell proliferation, migration, and new vessel formation in both normal development and tumor vascularization.
Molecular Mechanism
Mechanism Summary
HIF-1α-driven VEGFA secretion activates VEGFR2 on endothelial cells, triggering PLCγ/PKC, PI3K/AKT, and SRC/FAK cascades that drive endothelial proliferation, migration, and lumen formation — the core angiogenic switch enabling tumour growth beyond 1–2 mm.
Step-by-Step Mechanism
Secreted VEGFA165 (dominant isoform) diffuses to adjacent endothelial cells and binds VEGFR2 (KDR) extracellular Ig domains 2–3, inducing receptor homodimerisation and kinase domain activation.
VEGFR2 autophosphorylates at Tyr1054/Tyr1059 (kinase activation loop), Tyr951 (TSAd adaptor binding), and Tyr1175 (PLCγ and Shb binding sites).
PLCγ–Tyr1175 interaction activates PLCγ, generating IP3 and DAG. IP3 releases Ca2+ from ER, activating eNOS (endothelial nitric oxide synthase) to produce NO for vasodilation. DAG activates PKC, promoting MAPK/ERK-driven endothelial proliferation.
Shb adaptor at Tyr1175 activates PI3K/AKT, phosphorylating eNOS at Ser1177 for additional NO production and activating survival pathways in endothelial cells.
VEGFR2-mediated SRC activation promotes VE-cadherin Tyr685 phosphorylation, loosening endothelial adherens junctions and increasing vascular permeability — enabling plasma protein extravasation and provisional matrix formation needed for sprouting angiogenesis.
Upstream Regulators
Primary transcriptional activators of VEGFA via HRE binding; activated by hypoxia or VHL loss
Oncogenic RAS signalling drives VEGFA mRNA transcription and stabilisation
Wild-type p53 represses VEGFA; p53 loss enhances VEGFA expression
Downstream Targets
Primary signalling receptor; endothelial proliferation, migration, permeability
Decoy receptor sequestering VEGFA; also signals in macrophages and tumour cells
Co-receptor enhancing VEGFA/VEGFR2 complex assembly and signalling
Key Post-Translational Modifications
VEGFA121 (diffusible, no heparin binding) vs VEGFA165 (major angiogenic isoform) vs VEGFA189 (ECM-sequestered)
Release of matrix-bound VEGFA stores; rapid angiogenic burst
Disease Mechanism
Tumour VEGFA drives the angiogenic switch beyond which solid tumours cannot grow (>1–2 mm without neovascularisation). Bevacizumab (anti-VEGFA antibody) is approved for colorectal, lung, cervical, and ovarian cancers. Resistance arises through VEGF-independent angiogenic signals (FGF2, PDGF, angiopoietins) and vessel co-option. VEGFR2 TKIs (sunitinib, axitinib, cabozantinib) block intracellular signalling and are approved for RCC, HCC, and thyroid cancer.
Database References
Key Pathways
- ·Angiogenesis
- ·VEGF signaling
- ·HIF-1 signaling
- ·PI3K-AKT signaling
Disease Associations
- ·Cancer angiogenesis
- ·Age-related macular degeneration
- ·Diabetic retinopathy
Research Activity
VEGFA is an actively studied target: about 175+ clinical trials that mention it are currently recruiting on ClinicalTrials.gov. Trial activity reflects research interest, not proven benefit — designs, endpoints and populations vary widely.
Track VEGFA trials
New and changed oncology trials, summarised in plain language each day.
Functional Partners
Common Questions About VEGFA
What is VEGFA and why is it important in cancer?
VEGFA is the primary driver of tumour angiogenesis — the formation of new blood vessels that supply oxygen and nutrients to growing tumours. Tumours cannot grow beyond 1–2mm without neovascularisation; VEGFA secretion by tumour and stromal cells recruits endothelial cells to sprout new capillaries into the tumour mass.
How is VEGFA regulated by hypoxia?
Hypoxia stabilises HIF-1α (by inhibiting the PHD enzymes that normally tag it for degradation), and HIF-1α directly activates VEGFA transcription. This creates a positive feedback loop: tumour growth causes hypoxia, which induces VEGFA, which drives angiogenesis that supports further tumour expansion.
What drugs target VEGFA?
Bevacizumab (Avastin) is a monoclonal antibody that neutralises circulating VEGFA, blocking tumour angiogenesis, and is used in colorectal, lung, and ovarian cancers. Small-molecule VEGFR tyrosine kinase inhibitors (sunitinib, sorafenib, axitinib) block intracellular signalling downstream of all VEGF receptors.