[HTML][HTML] CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development

T Tu, C Zhang, H Yan, Y Luo, R Kong, P Wen, Z Ye… - Cell research, 2015 - nature.com
T Tu, C Zhang, H Yan, Y Luo, R Kong, P Wen, Z Ye, J Chen, J Feng, F Liu, JY Wu, X Yan
Cell research, 2015nature.com
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 …
Abstract
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 involvement of netrin-CD146 signaling in angiogenesis during vertebrate development.
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