Vascular endothelial growth factor receptor (VEGFR) (VEGFR)

The Vascular Endothelial Growth Factor (VEGF) receptor pathway is a fundamental signaling system that governs the formation of new blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) (NIH, 2020). It comprises several ligands, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF), which interact with three primary receptor tyrosine kinases: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4) (Frontiers in Oncology, 2020). VEGFR-2 is the primary mediator of the mitogenic, survival, and permeability-enhancing effects of VEGF on vascular endothelial cells, while VEGFR-3 is the key regulator of the lymphatic system (NIH, 2020). In pathological conditions, particularly cancer, tumors overexpress VEGF to stimulate the growth of a blood supply necessary for tumor expansion and metastasis (AACR, 2006). This pathway is also a major driver of ocular diseases such as wet age-related macular degeneration and diabetic retinopathy, where abnormal vessel growth leads to vision loss (NIH, 2011). Therapeutic strategies targeting this pathway include monoclonal antibodies that neutralize VEGF ligands, decoy receptors that sequester circulating growth factors, and small-molecule tyrosine kinase inhibitors that block intracellular signaling (NIH, 2022). While these therapies are effective in treating various malignancies and retinopathies, they are associated with systemic side effects such as hypertension and proteinuria, reflecting the physiological role of VEGF in maintaining vascular and renal homeostasis (AHA, 2017).

Other names

VEGF receptorVascular permeability factor receptorFms-like tyrosine kinaseKinase insert domain receptorFetal liver kinase 1Flt-1KDRFlt-4VEGF/VEGFR pathway

The pathway is targeted through several mechanisms: direct neutralization of VEGF ligands by monoclonal antibodies or decoy receptors to prevent receptor binding; blockade of the extracellular domain of VEGFR-2 by monoclonal antibodies; and inhibition of the intracellular tyrosine kinase domain of VEGFRs by small-molecule inhibitors to prevent downstream signaling (NIH, 2022; AHA, 2017).