Vascular endothelial growth factor receptor and co-receptor (VEGFR and NRP) (VEGFR/NRP)

The vascular endothelial growth factor (VEGF) receptor and co-receptor system is a complex network of cell-surface proteins that orchestrate the development and maintenance of the vascular and lymphatic systems [1, 6]. This system primarily consists of three high-affinity receptor tyrosine kinases—VEGFR-1 (Flt-1), VEGFR-2 (KDR), and VEGFR-3 (Flt-4)—alongside non-tyrosine kinase co-receptors known as neuropilins (NRP-1 and NRP-2) [1, 11]. VEGFR-2 is the central transducer of pro-angiogenic signals, promoting endothelial cell proliferation, migration, and survival, while VEGFR-3 is the primary regulator of lymphangiogenesis [9, 12]. Neuropilins function as essential co-receptors that bind specific VEGF isoforms, such as VEGF-A165, and present them to the signaling receptors to enhance pathway activation [3, 15]. In many diseases, particularly solid tumors, the dysregulation of this system leads to pathological angiogenesis, which supports tumor growth and facilitates metastatic spread [2, 16]. Therapeutic strategies targeting these receptors include monoclonal antibodies that block ligand binding (e.g., ramucirumab) and small-molecule inhibitors that target the intracellular kinase domains (e.g., sunitinib, sorafenib) [1, 17]. While highly effective in treating various cancers and neovascular eye diseases, these therapies are associated with significant safety concerns, such as hypertension and impaired wound healing, due to the systemic inhibition of physiological VEGF signaling [16, 17].

Other names

Vascular endothelial growth factor receptor 1 (VEGFR-1)Vascular endothelial growth factor receptor 2 (VEGFR-2)Vascular endothelial growth factor receptor 3 (VEGFR-3)Neuropilin-1 (NRP1)Neuropilin-2 (NRP2)Fms-like tyrosine kinase 1 (FLT1)Kinase insert domain receptor (KDR)Fms-like tyrosine kinase 4 (FLT4)Heparan sulfate proteoglycan (HSPG)VEGF receptorsNeuropilins

Inhibition of receptor tyrosine kinase activity, blockade of ligand-receptor binding, inhibition of receptor dimerization, and modulation of downstream signaling pathways such as PLCγ-PKC-MAPK and PI3K-Akt [1, 12, 17].