Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism
Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism
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DOI：
10.1073/pnas.0511011103
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发表时间：
2006-04-25
影响因子：
11.1
通讯作者：
Cai, H
中科院分区：
文献类型：
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作者：
Nguyen, A;Cai, H
Netrin-1在轴突的寻路中起关键作用，它与血管网络的形成有相似之处。在这里，我们报道了netrin-1诱导血管生成是由内皮一氧化氮(NO中心点)的增加介导的，这种增加是通过依赖于DCC的ERK1/2-eNOS前馈机制发生的。通过电子自旋共振检测，成熟的主动脉内皮细胞暴露于netrin-1后，NO中心点的产生明显增加，且呈剂量依赖性。用2-phenyl-4，4，5，5-tetramethylimidazoline-loxyl-3-oxide(PTIO)清除NO中心点可阻断Netrin-1刺激的血管生成。DCC抗体、DCC小干扰RNA(SiRNA)、MEK1/2的特异性抑制剂(PD98059、U0126)或MEK1/2的siRNAs均能抑制Netrin-1刺激的NO中心点的产生或血管生成。PTIO抑制ERKII/2的磷酸化，提示一种前馈机制。Netrin-1诱导eNOS(S1179)，0，6的时间依赖性磷酸化和eNOS的快速去磷酸化(T497)。只有eNOS(S1179)对U0126或PTIO敏感。这些数据描述了Netrin-1促进血管生成的机制，这可能与心血管、神经和癌症生理学广泛相关。
Netrin-1 is critical for axonal pathfinding which shares similarities with formation of vascular network. Here we report that netrin-1 induction of angiogenesis is mediated by an increase in endothelial nitric oxide (NO center dot) production, which occurs via a DCC-dependent, ERK1/2-eNOS feed-forward mechanism. Exposure of mature aortic endothelial cells to netrin-1 resulted in a potent, dose-dependent increase in NO center dot production, detected by electron spin resonance. Scavenging NO center dot with 2-phenyl-4,4,5,5-tetramethylimidazoline-loxyl-3-oxide (PTIO) abolished netrin-1 stimulated angiogenesis. Netrin-1-stimulated NO center dot production or angiogenesis was inhibited by DCC antibody, DCC small interfering RNA (siRNA), specific inhibitors (PD98059, U0126), or siRNAs for MEK1/2. PTIO attenuated ERKII/2 phosphorylation, indicating a feed-forward mechanism. Netrin-1 induced a time-dependent phosphorylation of eNOS(s1179), 0,6 and a rapid dephosphorylation of eNOS(t497). Only eNOS(s1179) was sensitive to U0126 or PTIO. These data characterized a mechanism whereby netrin-1 promotes angiogenesis, which may broadly relate to cardiovascular, neuronal and cancer physiology.