Vascular endothelial growth factor (VEGF) signaling axis (VEGF)

The Vascular Endothelial Growth Factor (VEGF) signaling axis is a fundamental regulator of both physiological and pathological angiogenesis (UniProt P15692) [1]. It consists of a family of secreted glycoproteins, most notably VEGF-A, and their cognate receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3 (PubMed: 15098007) [2]. Activation of this axis, particularly through the VEGF-A/VEGFR-2 interaction, triggers intracellular signaling cascades such as the MAPK and PI3K/Akt pathways that promote endothelial cell survival, proliferation, and migration. In many cancers, tumors overexpress VEGF to induce the formation of new blood vessels, a process essential for tumor growth beyond a few millimeters and for metastatic spread (Nature Reviews Cancer, 2002) [3]. Therapeutic inhibition of this axis, using agents such as bevacizumab or sunitinib, has become a standard of care in treating various solid tumors and neovascular ocular diseases like wet age-related macular degeneration (FDA) [5]. However, because VEGF also maintains normal vascular function, its inhibition can lead to systemic side effects such as hypertension and proteinuria (Journal of Clinical Oncology, 2009) [6].

Other names

VEGF/VEGFR signaling pathwayVascular endothelial growth factor pathwayVEGF signaling axisAngiogenesis axisVascular permeability factor (VPF) axis

The axis is targeted by either sequestering the VEGF ligands (e.g., VEGF-A) using monoclonal antibodies or decoy receptors to prevent receptor binding, or by inhibiting the intracellular tyrosine kinase activity of the VEGF receptors (VEGFR-1, -2, -3) using small molecules to block downstream signal transduction (StatPearls, 2023) [4].