VEGFA

VEGFA, or vascular endothelial growth factor A, is a secreted glycoprotein that stimulates angiogenesis and vasculogenesis. It is a key mediator of blood vessel formation during development and in adult tissue remodeling, influencing endothelial cell proliferation, migration, and survival, as well as vascular permeability.

VEGFA is encoded by the VEGFA gene on chromosome 6p21.1. The protein forms homodimers and is secreted into the extracellular space, where it binds to the receptor tyrosine kinases VEGFR1 (FLT1) and VEGFR2 (KDR/VEGFR2). Co-receptors neuropilin-1 and neuropilin-2 modulate signaling. Among the receptors, VEGFR2 is the principal mediator of mitogenic and survival signals that drive angiogenesis. VEGF-A also regulates vascular permeability and plays a role in lymphangiogenesis in certain contexts.

Signaling through VEGF receptors activates multiple pathways, including PI3K-AKT, PLCγ-PKC, and RAS-RAF-MEK-ERK, leading to endothelial proliferation, migration, and survival. VEGFA expression is tightly regulated; hypoxia induces its expression via HIF-1α and HIF-2α, linking tissue oxygen demand to vascular growth. VEGF-A exists as multiple isoforms due to alternative splicing, most notably VEGF-A121, VEGF-A165, and VEGF-A189, which differ in diffusibility and receptor-binding properties. Some splice variants, such as VEGF-A165b, have anti-angiogenic properties. The protein also interacts with the extracellular matrix through a heparin-binding domain, affecting diffusion and gradient formation.

Clinical relevance includes pathologic VEGFA upregulation in tumor angiogenesis and ocular neovascular diseases, such as age-related macular degeneration and diabetic retinopathy. Therapies targeting VEGFA signaling include anti-VEGF antibodies (bevacizumab, ranibizumab), fusion decoy receptors (aflibercept), and multi-target tyrosine kinase inhibitors (sunitinib, sorafenib). Potential adverse effects include hypertension and thromboembolic events.