VEGFRs

VEGFRs, or vascular endothelial growth factor receptors, are receptor tyrosine kinases that mediate responses to the vascular endothelial growth factor (VEGF) ligands. In mammals, the VEGF receptor family comprises VEGFR-1 (FLT1), VEGFR-2 (KDR/FLK1), and VEGFR-3 (FLT4). VEGFRs are mainly expressed on endothelial cells and regulate angiogenesis and lymphangiogenesis; VEGFR-2 is the principal mediator of new blood vessel formation, while VEGFR-3 primarily controls lymphatic vessel growth. VEGFR-1 functions mainly as a high-affinity VEGF-A-binding receptor and modulates signaling rather than acting as a primary angiogenic effector; it also binds placental growth factor (PlGF).

All VEGFRs share a common structure: an extracellular domain with Ig-like motifs, a single transmembrane region, and an intracellular tyrosine kinase domain. Ligand binding induces receptor dimerization and autophosphorylation of tyrosine residues, triggering intracellular signaling. Common downstream pathways include PI3K–AKT, Ras–MAPK, and PLCγ, which promote endothelial proliferation, migration, survival, and increased vascular permeability. Neuropilins (NRP1, NRP2) act as co-receptors that enhance VEGF–VEGFR signaling without possessing intrinsic kinase activity.

VEGF ligands include VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF). VEGF-A binds VEGFR-1 and VEGFR-2; VEGF-C and VEGF-D preferentially activate VEGFR-3, linking ligand availability to angiogenesis or lymphangiogenesis.

Dysregulated VEGF–VEGFR signaling contributes to diseases such as cancer and ocular neovascular disorders. Anti-angiogenic therapies target VEGF ligands or VEGFRs, including monoclonal antibodies against VEGF-A and tyrosine kinase inhibitors of VEGFRs. Resistance can arise through alternative pro-angiogenic pathways or receptor alterations.