Inhibition of Endothelial Cell Apoptosis by Netrin-1 during Angiogenesis
Inhibition of Endothelial Cell Apoptosis by Netrin-1 during Angiogenesis
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DOI：
10.1016/j.devcel.2009.02.006
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发表时间：
2009-04-21
影响因子：
11.8
通讯作者：
Mehlen, Patrick
中科院分区：
文献类型：
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作者：
Castets, Marie;Coissieux, Marie-May;Mehlen, Patrick
Netrin-1最近被认为在胚胎和病理性血管生成中起重要作用。然而，报告的数据导致了netrin-1是促血管生成因子或抗血管生成因子的明显矛盾的结论。在这里，我们通过证明netrin-1作为内皮细胞的存活因子，阻断依赖性受体UNC 5 B及其下游死亡信号效应子丝氨酸/苏氨酸激酶DAPK的促凋亡作用来调和这些相反的观察结果。netrin-1对血管发育的作用在离体测定中被半胱天冬酶抑制剂模拟，并且半胱天冬酶活性的抑制、UNC 5 B受体的沉默和DAPK的沉默各自足以挽救斑马鱼中由netrin-1沉默诱导的血管发芽缺陷。因此，未结合的UNC 5 B的促凋亡作用和netrin-1对内皮细胞的存活作用精细地调节血管生成过程。
Netrin-1 was recently proposed to play an important role in embryonic and pathological angiogenesis. However, data reported led to the apparently contradictory conclusions that netrin-1 is either a pro- or an antiangiogenic factor. Here, we reconcile these opposing observations by demonstrating that netrin-1 acts as a survival factor for endothelial cells, blocking the proapoptotic effect of the dependence receptor UNC5B and its downstream death signaling effector, the serine/threonine kinase DAPK. The netrin-1 effect on blood vessel development is mimicked by caspase inhibitors in ex vivo assays, and the inhibition of caspase activity, the silencing of the UNC5B receptor, and the silencing of DAPK are each sufficient to rescue the vascular sprouting defects induced by netrin-1 silencing in zebrafish. Thus, the proapoptotic effect of unbound UNC5B, and the survival effect of netrin-1 on endothelial cells finely tune the angiogenic process.