SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis.
SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis.
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VEGFR2 的 SUMO 化调节其细胞内运输和病理性血管生成
DOI：
10.1038/s41467-018-05812-2
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发表时间：
2018-08-17
影响因子：
16.6
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
Zhou HJ;Xu Z;Wang Z;Zhang H;Zhuang ZW;Simons M;Min W
VEGFR2的调控是调控血管生成的重要机制。VEGFR2的活性可以通过翻译后修饰来调节，如泛素化和乙酰化。然而，VEGFR2是否可以被SUMO化调控，目前还没有研究。在这里，我们表明，内皮特异性的相扑内肽酶SENP1的缺失减少了后肢缺血期间的病理性血管生成和组织修复，以及血管内皮生长因子诱导的角膜、视网膜和耳朵的血管生成。SENP1缺陷的内皮细胞表现出VEGFR2 SUMO化增加和VEGFR2信号减弱。赖氨酸1270上的苏莫化在高尔基体中保留了VEGFR2，并减少了其表面表达，减弱了VEGFR2依赖的信号转导。此外，我们发现在糖尿病环境中SENP1下调和VEGFR2高SUMO化，并且非SUMO化形式的VEGFR2的表达挽救了糖尿病小鼠的血管生成缺陷。这些结果表明，VEGFR2在病理性血管生成过程中受去SUMO调节，提示SENP1可作为治疗糖尿病相关血管生成的潜在靶点。
Regulation of VEGFR2 represents an important mechanism for the control of angiogenesis. VEGFR2 activity can be regulated by post-translational modifications such as ubiquitination and acetylation. However, whether VEGFR2 can be regulated by SUMOylation has not been investigated. Here we show that endothelial-specific deletion of the SUMO endopeptidase SENP1 reduces pathological angiogenesis and tissue repair during hindlimb ischemia, and VEGF-induced angiogenesis in the cornea, retina, and ear. SENP1-deficient endothelial cells show increased SUMOylation of VEGFR2 and impaired VEGFR2 signalling. SUMOylation at lysine 1270 retains VEGFR2 in the Golgi and reduces its surface expression, attenuating VEGFR2-dependent signalling. Moreover, we find that SENP1 is downregulated and VEGFR2 hyper-SUMOylated in diabetic settings and that expression of a non-SUMOylated form of VEGFR2 rescues angiogenic defects in diabetic mice. These results show that VEGFR2 is regulated by deSUMOylation during pathological angiogenesis, and propose SENP1 as a potential therapeutic target for the treatment of diabetes-associated angiogenesis.
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