- Vascular Endothelial Growth Factor-A (VEGF-A) is the most well-studied and biologically significant member of the VEGF family, recognized as the primary driver of angiogenesis—the growth of new blood vessels from preexisting vasculature.
- It is a secreted glycoprotein that binds with high affinity to the receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) on endothelial cells, with VEGFR-2 being the major mediator of its pro-angiogenic effects. VEGF-A was initially identified as a potent inducer of vascular permeability, earning it the alternative name vascular permeability factor (VPF).
- At the molecular level, VEGF-A is regulated by tissue oxygen availability. Hypoxia is its strongest stimulus, acting primarily through the hypoxia-inducible factor-1 (HIF-1) pathway. Under low oxygen conditions, HIF-1 activates VEGF-A gene transcription, ensuring that oxygen-deprived tissues can promote the growth of new blood vessels to restore perfusion. This mechanism is critical in embryonic development, wound healing, and tissue repair after ischemic injury. VEGF-A exists in several splice variants (such as VEGF121, VEGF165, VEGF189), which differ in their ability to bind heparin and extracellular matrix components, thereby influencing their bioavailability and activity.
- Physiologically, VEGF-A stimulates endothelial cell proliferation, migration, and survival, enabling the sprouting and branching of new vessels. It also enhances vascular permeability by reorganizing endothelial junctions and increasing fenestrations, which allows plasma proteins to leak into the interstitial space. This leakage provides a scaffold for endothelial migration and new vessel formation. Beyond angiogenesis, VEGF-A has roles in hematopoiesis, neurogenesis, and reproductive biology, further underscoring its wide-ranging influence.
- Pathologically, VEGF-A is a central mediator in diseases characterized by abnormal or excessive angiogenesis. In cancer, tumor cells secrete VEGF-A to stimulate the development of a chaotic but functional blood supply that supports tumor growth and provides routes for metastasis. In ophthalmic diseases such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion, VEGF-A drives the growth of fragile, leaky vessels in the retina and choroid, leading to vision loss. Excessive VEGF-A activity is also implicated in chronic inflammatory disorders, rheumatoid arthritis, and psoriasis, where pathological neovascularization worsens disease progression.
- Given its central role, VEGF-A has become one of the most important therapeutic targets in medicine. Anti-VEGF therapies have revolutionized cancer treatment and ophthalmology. In oncology, agents such as bevacizumab (a monoclonal antibody against VEGF-A) and small-molecule tyrosine kinase inhibitors targeting VEGFR signaling have been widely used to inhibit tumor angiogenesis. In eye diseases, intravitreal injections of anti-VEGF agents such as ranibizumab, aflibercept, and bevacizumab are standard treatments to prevent vision loss by suppressing abnormal retinal angiogenesis and vascular leakage. Conversely, strategies to enhance VEGF-A activity are being explored in regenerative medicine to promote therapeutic angiogenesis in ischemic heart disease, stroke, and peripheral artery disease.
