Plasmin activates VEGF-C and VEGF-D

Abstract Angiogenesis and lymphangiogenesis (growth of lymphatic vessels) are guided by members of the vascular endothelial growth factor (VEGF) family of secreted glycoproteins. In particular, VEGF-C and VEGF-D promote lymphangiogenesis as demonstrated in transgenic animal models and gene delivery studies. VEGF-C and VEGF-D are secreted as full-length forms that require proteolytic activation for high affinity binding to VEGF receptor-2 (VEGFR-2) and VEGFR-3, cell surface receptor tyrosine kinases localised on the endothelial cells of blood vessels and lymphatics. The proteases that activate these lymphangiogenic growth factors are key regulators of lymphatic development but were previously unknown. Here we report identification of the serine protease plasmin as an enzyme capable of activating both VEGF-C and VEGF-D.