Vascular endothelial growth factor A – Vascular endothelial growth factor receptor axis (VEGF-A – VEGFR axis) (VEGF-A – VEGFR axis)

The Vascular endothelial growth factor A – Vascular endothelial growth factor receptor axis (VEGF-A – VEGFR axis) is a critical signaling pathway that governs the formation and maintenance of the blood vessel network [1, 2]. It primarily involves the ligand VEGF-A and its two main receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), which are predominantly expressed on the surface of vascular endothelial cells [2, 4]. Binding of VEGF-A to VEGFR-2 is the primary driver of angiogenesis, initiating intracellular signaling cascades that promote endothelial cell proliferation, migration, and survival, while also increasing vascular permeability [6, 8]. In pathological conditions such as cancer, tumors overexpress VEGF-A to stimulate the growth of new blood vessels, a process essential for tumor expansion and metastatic spread [5, 10]. This axis is also a central mediator of neovascularization in ocular diseases, including wet age-related macular degeneration and diabetic retinopathy [3, 12]. Therapeutic strategies targeting this axis include monoclonal antibodies that neutralize the ligand, decoy receptors that sequester circulating VEGF, and small-molecule inhibitors that block the intracellular kinase activity of the receptors [1, 8]. While these therapies have revolutionized the treatment of various malignancies and blinding eye diseases, they are associated with systemic safety concerns such as hypertension and proteinuria due to the role of VEGF in maintaining normal vascular and renal homeostasis [8, 15].

Other names

VEGF/VEGFR axisVEGF signaling pathwayVEGF-A/VEGFR-2 axisVascular permeability factor (VPF) axis

Drugs targeting the VEGF-A – VEGFR axis function by neutralizing the extracellular ligand VEGF-A to prevent receptor binding, acting as decoy receptors (traps) to sequester the ligand, or inhibiting the intracellular tyrosine kinase activity of the receptors (VEGFR-1/2) to block downstream signaling cascades such as the MAPK and PI3K/Akt pathways [1, 3, 8].