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

The Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR) constitute a fundamental signaling system that regulates the growth and maintenance of the vascular and lymphatic systems (UniProt P15692, P35968). The VEGF family includes several ligands, most notably VEGF-A, which bind to three primary receptor tyrosine kinases: VEGFR-1 (Flt-1), VEGFR-2 (KDR), and VEGFR-3 (Flt-4). VEGFR-2 is the principal mediator of pro-angiogenic signaling, driving endothelial cell proliferation, migration, and survival, as well as increasing vascular permeability (Ferrara, N., & Adamis, A. P., 2016, Nature Reviews Drug Discovery). In oncology, tumors frequently overexpress VEGF to induce neoangiogenesis, which is essential for tumor growth beyond a few millimeters and for metastatic spread. Similarly, excessive VEGF activity is the primary driver of pathological neovascularization in ocular diseases such as wet age-related macular degeneration and diabetic retinopathy (Apte, R. S., et al., 2019, Cell). Consequently, the VEGF/VEGFR axis is one of the most successfully drugged pathways in modern medicine, with therapies ranging from injectable biologics for eye disease to systemic antibodies and small-molecule kinase inhibitors for various solid tumors. However, because VEGF signaling is also required for normal physiological vascular homeostasis, these treatments are often associated with class-specific toxicities such as hypertension and impaired wound healing (StatPearls, 2023, Angiogenesis Inhibitors).

Other names

Vascular permeability factorVPFKinase insert domain receptorKDRFms-like tyrosine kinase 1FLT1Fms-like tyrosine kinase 4FLT4VEGF signaling axis

Therapeutic agents target this axis through three primary mechanisms: ligand sequestration using monoclonal antibodies or decoy receptors to prevent VEGF from binding to its receptors; receptor blockade using antibodies that bind directly to the extracellular domain of VEGFR; and intracellular inhibition of the receptor's tyrosine kinase activity using small-molecule inhibitors to block downstream signaling pathways such as MAPK/ERK and PI3K/Akt (Ferrara, N., 2004, Nature Reviews Cancer; StatPearls, 2023).