Gene Number: 7422

Location: 6p21.1

Key Functions: Angiogenesis, vascular permeability, endothelial cell proliferation, wound healing, cardiovascular and tissue homeostasis

VEGFA encodes vascular endothelial growth factor A, a potent signaling molecule central to the process of angiogenesis—the formation of new blood vessels from pre-existing vasculature. It acts as a key regulator of vascular integrity, endothelial cell survival, and tissue oxygenation. VEGFA’s biological actions are primarily mediated through its binding to VEGFR1 (FLT1) and VEGFR2 (KDR/FLK1) receptors on endothelial cells, which activate downstream signaling cascades, including PI3K/AKT, MAPK/ERK, and PLCγ pathways, resulting in endothelial proliferation, migration, and vessel formation.

VEGFA is transcriptionally upregulated under hypoxic conditions via HIF-1α activation, allowing tissues to adapt to low oxygen availability by stimulating local angiogenesis and restoring perfusion. Additionally, VEGFA increases vascular permeability, enabling plasma protein leakage and extracellular matrix remodeling essential for vessel sprouting and tissue regeneration. Balanced VEGFA expression is thus indispensable for maintaining cardiovascular health, wound healing, and neurovascular integrity.

Pathophysiological relevance:Dysregulation of VEGFA signaling contributes to a spectrum of diseases. Overexpression is associated with tumor angiogenesis, diabetic retinopathy, and rheumatoid arthritis, whereas reduced expression can lead to impaired wound healing, tissue ischemia, and microvascular rarefaction. Proper modulation of VEGFA activity is therefore crucial for both vascular and systemic homeostasis.

Genetic variation and clinical implications:Variants in VEGFA can significantly affect vascular function and influence the risk of various diseases, particularly cardiovascular disorders, cancer, and diabetic complications such as retinopathy. These genetic polymorphisms modulate angiogenic signaling efficiency and endothelial responsiveness, altering the balance of blood vessel formation and maintenance.

For instance, allelic variants such as rs699947, rs2010963, and rs3025039 have been shown to enhance or suppress VEGFA expression, thereby modifying angiogenic potential. Individuals harboring high-expression variants may demonstrate increased susceptibility to tumor growth and metastasis, driven by excessive neovascularization, whereas low-expression alleles are linked to microvascular dysfunction and impaired tissue repair. In diabetes, such alterations can exacerbate retinal microangiopathy, contributing to diabetic retinopathy, a leading cause of vision loss.

Understanding the molecular and functional consequences of VEGFA polymorphisms provides essential insight for targeted therapeutic development and personalized medicine approaches, aiming to restore angiogenic balance and mitigate disease progression associated with abnormal vascular function.