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

• Published in: Cell research Vol. 25; no. 3; pp. 275 - 287
• Main Authors: Tu, Tao, Zhang, Chunxia, Yan, Huiwen, Luo, Yongting, Kong, Ruirui, Wen, Pushuai, Ye, Zhongde, Chen, Jianan, Feng, Jing, Liu, Feng, Wu, Jane Y, Yan, Xiyun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2015; Nature Publishing Group
• Subjects: 631/136/2060/16; 631/337; 631/80/86; Animals; Biomedical and Life Sciences; CD146 Antigen - genetics; CD146 Antigen - metabolism; Cell Biology; Cell Line; Cell Movement; Cell Proliferation; HEK293 Cells; Human Umbilical Vein Endothelial Cells - physiology; Humans; Life Sciences; Mice; Mice, Transgenic; Neovascularization, Physiologic - genetics; Neovascularization, Physiologic - physiology; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Netrin Receptors; Netrin-1; Original; original-article; Protein Binding; Receptors, Cell Surface - genetics; RNA Interference; RNA, Small Interfering; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vertebrates; Zebrafish; Zebrafish Proteins; 免疫球蛋白超家族; 受体介导; 抗血管生成; 脊椎动物; 芽诱导; 血管发育; 血管系统; 跨膜蛋白; vascular development; CD146; angiogenesis; netrin-1
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2015.15

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. Condi- tional 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-l-induced angiogenesis. In zebrafish embryos, downregulating either netrin-la 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.