Vascular endothelial growth factor receptor 1 and 2 (VEGFR1/VEGFR2)

Vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2) are essential receptor tyrosine kinases (RTKs) that regulate the development and maintenance of the vascular system (UniProt P17948, P35968). VEGFR2 (KDR/Flk-1) is the primary mediator of the pro-angiogenic effects of VEGF, including endothelial cell proliferation, migration, and survival, as well as increased vascular permeability (PubMed: 11544348). VEGFR1 (Flt-1) has a higher affinity for VEGF but lower kinase activity, often acting as a decoy receptor to sequester VEGF, though it also plays roles in recruiting hematopoietic stem cells and modulating inflammation (PubMed: 10666492). In many cancers, these receptors are overexpressed on both the tumor-associated endothelial cells and the tumor cells themselves, driving the pathological angiogenesis required for tumor growth and metastasis (StatPearls: Angiogenesis Inhibitors). Therapeutic targeting of these receptors, primarily through small-molecule tyrosine kinase inhibitors (TKIs) like sunitinib or monoclonal antibodies like ramucirumab, aims to disrupt these signaling pathways to inhibit tumor vascularization. Because these receptors are also expressed in normal tissues, their inhibition can lead to systemic side effects such as hypertension and impaired wound healing. These targets are also critical in ophthalmology, where anti-VEGF therapies are used to treat wet age-related macular degeneration by preventing abnormal vessel growth in the retina. Overall, VEGFR1 and VEGFR2 represent cornerstone targets in anti-angiogenic therapy across multiple solid tumor types and vascular diseases.

Other names

Fms-like tyrosine kinase 1FLT1Kinase insert domain receptorKDRFetal liver kinase 1FLK1CD309Vascular endothelial growth factor receptor

Inhibition of the intracellular tyrosine kinase domain of VEGFR1 and VEGFR2, or blocking the extracellular ligand-binding domain, to prevent VEGF-mediated signaling pathways such as MAPK/ERK and PI3K/Akt, thereby inhibiting angiogenesis and tumor growth.