- Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2, also called KDR in humans and Flk-1 in mice) is the principal mediator of angiogenesis among the VEGF receptor family.
- It is a receptor tyrosine kinase expressed mainly on endothelial cells and is responsible for most of the mitogenic, angiogenic, and permeability-enhancing effects of VEGF.
- Its main ligand is VEGF-A, although VEGF-C and VEGF-D can also activate it under certain conditions.
- Structurally, VEGFR-2 has the classic features of receptor tyrosine kinases: an extracellular domain with multiple immunoglobulin-like loops that bind VEGF, a single transmembrane region, and an intracellular tyrosine kinase domain with several autophosphorylation sites. When VEGF-A binds to VEGFR-2, the receptor undergoes dimerization and autophosphorylation, initiating several key signaling cascades. These pathways include:
- MAPK/ERK pathway → endothelial cell proliferation.
- PI3K/AKT pathway → cell survival and anti-apoptotic effects.
- PLCγ/PKC pathway → increased vascular permeability and nitric oxide production.
- Through these pathways, VEGFR-2 drives the sprouting of new vessels, the survival of endothelial cells, and the regulation of vascular tone.
- Functionally, VEGFR-2 is the workhorse receptor for angiogenesis. During embryonic development, it is essential for vasculogenesis (the formation of the first blood vessels) and subsequent angiogenesis. In adults, it is activated in wound healing and tissue repair but also in many pathological conditions. Tumors, for example, release large amounts of VEGF-A, which activates VEGFR-2 on nearby endothelial cells to stimulate the growth of new, abnormal blood vessels that supply oxygen and nutrients to cancer tissue. Similarly, VEGFR-2 activation contributes to the abnormal retinal neovascularization seen in diseases like age-related macular degeneration (AMD) and diabetic retinopathy.
- From a clinical perspective, VEGFR-2 is one of the most important therapeutic targets in oncology and ophthalmology. Anti-VEGF strategies—including monoclonal antibodies against VEGF (e.g., bevacizumab), soluble VEGF decoys (e.g., aflibercept), and small-molecule VEGFR tyrosine kinase inhibitors (e.g., sunitinib, sorafenib, pazopanib)—work largely by blocking VEGF-A/VEGFR-2 signaling. These treatments suppress tumor angiogenesis, slow tumor progression, and are also used to inhibit pathological ocular neovascularization.
