Vascular endothelial growth factor C (VEGF-C) and VEGF-D constitute a subfamily of vascularogenic VEGF growth factors. VEGF-C is combined into a 58 kDa molecule, consisting of a VEGF homologous domain (VHD), with N-terminal and C-terminal propeptides on both sides. The precursor protein undergoes covalent dimerization and progressive proteolysis to generate a ligand with enhanced affinity for VEGF R3/Flt-4. The fully processed VEGF-C contains only 21 kDa VHD and can additionally bind and activate VEGF R2/KDR/Flk-1. The fully processed human VEGF-C has 98% identical amino acid sequence to that of mouse and rat VEGF-C. The interaction of VEGF-C with VEGF R3 is crucial for lymphangiogenesis (5-8). VEGF-C and VEGF R3 are usually co-expressed during lymphangiogenesis, embryonic development, and various pathological conditions. Overexpression of VEGF-C in tumor cells can induce tumor lymphocyte proliferation, leading to increased lymph flow and metastasis to regional lymph nodes. It also induces physiological and tumor-specific angiogenesis and sprouting through interaction with VEGF R2.
