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Figure 1 Binding of VEGF Family Members to 3 High-Affinity Receptors on Endothelium and Downstream Signaling Cascades

The roles of vascular endothelial growth factor receptor (VEGFR)-2 and -3 as principal regulators of blood and lymphatic vessel effects of vascular endothelial growth factors (VEGFs) are well established, but the biology of VEGFR-1 is still poorly understood. VEGFR-1 appears to mediate ligand-specific actions. It also exists as a soluble decoy receptor and acts as a negative regulator of angiogenesis. However, VEGFR-1 activation by placental growth factor (PlGF) and VEGF-B stimulates vascular growth and may result in the mobilization of EPCs in vivo. VEGFR-1 also mediates monocyte chemotaxis. Neuropilin-1 and -2 are co-receptors for some VEGFs and amplify intracellular signals. Affinity to heparan sulfates and neuropilin co-receptors modulate the biological activities of different VEGFs. VEGF-C and -D are proteolytically processed into mature forms that also effectively bind to VEGFR-2. DAG = diacylglycerol; eNOS = endothelial nitric oxide synthase; EPC = endothelial precursor cell; IP₃ = inositol trisphosphate; MAPK = mitogen-activated protein kinase; NO = nitric oxide; NRP = neuropilin; PGI₂ = prostacyclin; PKC = protein kinase C; PLC = phospholipase gamma.