- Vascular endothelial growth factor receptors (VEGFRs) are a family of transmembrane receptor tyrosine kinases that mediate the effects of vascular endothelial growth factor (VEGF). They are primarily expressed on endothelial cells but can also be found on certain hematopoietic cells and, in some cases, tumor cells.
- VEGFRs are critical regulators of angiogenesis, lymphangiogenesis, vascular permeability, and endothelial cell survival. When VEGF ligands bind to these receptors, they induce receptor dimerization and autophosphorylation of intracellular tyrosine residues, which activates downstream signaling cascades that control endothelial cell proliferation, migration, and new vessel formation.
- There are three main VEGFR subtypes: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Among them, VEGFR-2 is considered the principal mediator of angiogenic signaling, responsible for most of the mitogenic, survival, and permeability-enhancing effects of VEGF. VEGFR-1 binds VEGF with high affinity but has weaker kinase activity; it may function as a “decoy receptor” in some contexts, modulating VEGF availability to VEGFR-2, while also playing roles in monocyte migration and inflammation. VEGFR-3, in contrast, is predominantly involved in lymphangiogenesis, mediating the growth of lymphatic vessels under both physiological and pathological conditions, and is mainly activated by VEGF-C and VEGF-D.
- Structurally, VEGFRs share common features with other receptor tyrosine kinases. They consist of an extracellular domain with multiple immunoglobulin-like loops for ligand binding, a single transmembrane domain, and an intracellular tyrosine kinase domain. Ligand binding promotes receptor dimerization, either as homodimers (VEGFR-2/VEGFR-2) or heterodimers (VEGFR-1/VEGFR-2), followed by phosphorylation of tyrosine residues. These phosphorylated sites serve as docking points for adaptor proteins, triggering multiple downstream signaling pathways, including the PI3K/AKT pathway for cell survival, the MAPK/ERK pathway for proliferation, and the PLCγ/PKC pathway for vascular permeability.
- Clinically, VEGFRs are central to disease processes where angiogenesis is dysregulated. In cancer, tumor cells stimulate VEGF production, which activates VEGFRs on surrounding endothelial cells to build new blood vessels that sustain tumor growth and metastasis. In ophthalmology, overactivation of VEGFR-2 contributes to abnormal retinal angiogenesis in age-related macular degeneration and diabetic retinopathy. Conversely, impaired VEGFR signaling can hinder wound healing or tissue repair. Because of this, VEGFRs have become major therapeutic targets. Several drugs—including monoclonal antibodies (e.g., bevacizumab targeting VEGF-A) and small-molecule tyrosine kinase inhibitors (e.g., sunitinib, sorafenib, pazopanib)—are designed to block VEGF/VEGFR interactions, effectively suppressing angiogenesis in cancer and ocular diseases.
