Vascular endothelial growth factor (VEGF) signaling pathway (VEGF/VEGFR)

The Vascular endothelial growth factor (VEGF) signaling pathway is a fundamental regulator of angiogenesis, the physiological process through which new blood vessels form from pre-existing vasculature (StatPearls: Angiogenesis Inhibitors, 2023). This pathway is primarily mediated by the binding of VEGF ligands—most notably VEGF-A—to their cognate transmembrane receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3 (UniProt: P15692). Upon ligand binding, these receptors undergo dimerization and autophosphorylation, triggering intracellular signaling networks such as the MAPK/ERK and PI3K/Akt pathways that drive endothelial cell proliferation, migration, and survival (PubMed: PMC6406668). In oncology, tumors often overexpress VEGF to stimulate the development of a dedicated blood supply, which is essential for tumor growth and metastatic spread (NIH: National Cancer Institute, 2023). Similarly, in ophthalmology, excessive VEGF signaling leads to the pathological neovascularization and vascular leakage characteristic of wet age-related macular degeneration and diabetic retinopathy. Therapeutic interventions include monoclonal antibodies that sequester VEGF ligands, decoy receptors like aflibercept, and small-molecule tyrosine kinase inhibitors (TKIs) that block receptor activity. While these therapies have revolutionized treatment for various cancers and blinding eye diseases, they carry significant safety risks, including systemic hypertension and impaired wound healing, due to the pathway's role in maintaining normal vascular homeostasis.

Other names

Vascular permeability factorVPFAngiogenic signalingVEGF-VEGFR axisVEGF pathway

Inhibition of VEGF ligands (e.g., VEGF-A) to prevent receptor binding, or competitive inhibition of the intracellular tyrosine kinase domain of VEGF receptors (VEGFR-1, -2, -3) to block downstream signaling cascades.