Vascular endothelial growth factor and vascular endothelial growth factor receptor signaling system (VEGF/VEGFR)

The Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR) constitute a critical signaling system that regulates the development and maintenance of the vascular and lymphatic systems (Simons, M., et al. Nature Reviews Molecular Cell Biology, 2016). This axis primarily involves the binding of VEGF ligands, such as VEGF-A, VEGF-B, and Placental Growth Factor (PlGF), to three high-affinity receptor tyrosine kinases: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4) (Ferrara, N., & Adamis, A. P. Nature Reviews Drug Discovery, 2016). Activation of these receptors, particularly VEGFR-2, triggers downstream signaling cascades like the MAPK and PI3K/Akt pathways, which promote endothelial cell proliferation, migration, and survival. In pathological states, such as solid tumors, the overproduction of VEGF drives "angiogenic switching," leading to the formation of disorganized and leaky blood vessels that support tumor growth and metastasis (Apte, R. S., et al. Cell, 2019). In ophthalmology, excessive VEGF signaling is a primary driver of neovascularization in conditions like age-related macular degeneration and diabetic retinopathy. Therapeutic strategies targeting this system include monoclonal antibodies that sequester VEGF ligands, decoy receptors, and small-molecule inhibitors that block the intracellular kinase activity of VEGFRs. While highly effective in treating various cancers and retinal diseases, systemic inhibition of this pathway is associated with notable side effects including hypertension, proteinuria, and impaired wound healing.

Other names

VEGF signaling pathwayVEGF pathwayVascular endothelial growth factor signaling axisAngiogenesis signaling system

Inhibition of the VEGF/VEGFR signaling axis through ligand sequestration using neutralizing monoclonal antibodies or decoy receptors, or through the inhibition of intracellular receptor tyrosine kinase activity using small molecule inhibitors.