Angiogenesis, a process that newly-formed blood vessels sprout from pre-existing ones, is vital for vertebrate development and adult homeostasis.Previous studies have demonstrated that the neuronal guidance molecule netrin-1 participates in angiogenesis and morphogenesis of the vascular system.Netrin-1 exhibits dual activities in angiogenesis: either promoting or inhibiting angiogenesis.The anti-angiogenic activity of netrin-1 is mediated by UNC5B receptor.However, how netrin-1 promotes angiogenesis remained unclear.Here we report that CD146, an endothelial transmembrane protein of the immunoglobulin superfamily, is a receptor for netrin-1.Netrin-1 binds to CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner.Conditional knockout of the cd146 gene in the murine endothelium or disruption of netrin-CD146 interaction by a specific anti-CD146 antibody blocks or reduces netrin-1-induced angiogenesis.In zebrafish embryos, downregulating either netrin-1a or CD146 results in vascular defects with striking similarity.Moreover, knocking down CD146 blocks ectopic vascular sprouting induced by netrin-1 overexpression.Together, our data uncover CD146 as a previously unknown receptor for netrin-1 and also reveal a functional ligand for CD146 in angiogenesis, demonstrating the involv ment of netrin-CD146 signaling in angiogenesis during vertebrate development.