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

Tao Tu, Chunxia Zhang, Huiwen Yan, Yongting Luo, Ruirui Kong, Pushuai Wen, Zhongde Ye, Jianan Chen, Jing Feng, Feng Liu, Jane Y. Wu*, Xiyun Yan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)275-287
Number of pages13
JournalCell Research
Volume25
Issue number3
DOIs
StatePublished - Mar 5 2015

Keywords

  • CD146
  • angiogenesis
  • netrin-1
  • vascular development

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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