Vascular endothelial growth factor A receptor 1, 2, and 3 (VEGF-A/VEGFR1-3)

Vascular endothelial growth factor A (VEGF-A) is a master regulator of angiogenesis and is expressed in many cell types including endothelial and tumor cells. It signals primarily through three receptor tyrosine kinases: VEGFR-1, VEGFR-2, and VEGFR-3, which are cell surface receptors with distinct ligand specificities and cellular roles. VEGF-A/VEGFR-2 signaling is the most potent driver of new blood vessel formation, promoting endothelial cell proliferation, migration, and survival. VEGF-A/VEGFR-1 participates mainly in moderating angiogenic responses and acts as a negative regulator of VEGFR-2 signaling. VEGF-A/VEGFR-3 works in lymphatic endothelial cells, although it primarily binds VEGF-C and VEGF-D. Agonist binding triggers receptor dimerization and autophosphorylation, sparking complex intracellular signaling cascades. VEGF-A/VEGFR signaling is critical for physiological processes (embryogenesis, wound healing, menstrual cycling) as well as pathological conditions (cancer angiogenesis, retinopathy, chronic inflammation). Structurally, VEGFRs share a similar architecture with seven immunoglobulin-like extracellular domains, a transmembrane region, and an intracellular split tyrosine kinase domain. The clinical importance of the VEGF-A/VEGFR axis is underscored by the wide use of these receptors as therapeutic targets in cancer and eye diseases, as well as the risks of serious adverse effects due to their fundamental role in vascular biology.

Other names

VEGF-A (vascular endothelial growth factor A, aka vascular permeability factor [VPF])VEGFR-1 (Flt-1)VEGFR-2 (KDR, Flk-1)VEGFR-3 (Flt-4)“VEGF receptors” (for the receptor family)

Ligand neutralization (antibodies/blockers prevent VEGF-A from binding receptor); Kinase inhibition (small molecules that inhibit VEGFR tyrosine kinase activity); Decoy receptors (fusion proteins bind VEGF-A and sequester it, e.g., aflibercept)