VEGFR

VEGFR refers to a family of receptor tyrosine kinases that bind vascular endothelial growth factors and regulate angiogenesis and lymphangiogenesis. The mammalian VEGFR family consists of VEGFR-1 (FLT1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (FLT4). Ligands include VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). VEGF-A primarily activates VEGFR-2 to promote endothelial proliferation, migration, and permeability; VEGF-C and VEGF-D preferentially activate VEGFR-3 to drive lymphangiogenesis, while VEGF-A and VEGF-B can bind VEGFR-1 with lower affinity. PlGF binds VEGFR-1.

All VEGFRs are single-pass transmembrane receptor tyrosine kinases. Binding of a VEGF ligand induces receptor dimerization and autophosphorylation of intracellular tyrosine residues, creating docking sites for SH2-domain proteins such as Grb2, PLCγ, SHB, and PI3K. Signaling through VEGFR-2 is considered the primary driver of angiogenesis, engaging the PI3K/AKT, PLCγ, and Ras/ERK pathways to promote endothelial survival, proliferation, migration, and vascular permeability. VEGFR-3 signaling mainly mediates lymphatic endothelial cell growth and remodeling; VEGFR-1 often modulates signaling and, in some contexts, acts as a decoy receptor.

Physiological roles include embryonic vasculogenesis, postnatal angiogenesis, tissue repair, and ocular vascular development. In pathology, VEGFR signaling contributes to tumor angiogenesis and other diseases characterized by aberrant vessel growth.

Therapeutically, the VEGF/VEGFR axis is targeted in cancer and ocular diseases with agents such as VEGFR-2–targeted antibodies and tyrosine kinase inhibitors that block VEGFR signaling. Inhibitors include ramucirumab (anti-VEGFR-2) and TKIs such as sunitinib, sorafenib, pazopanib, and axitinib. Common adverse effects relate to impaired angiogenesis, including hypertension, thrombosis, wound-healing impairment, and proteinuria.