Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells
Yes-Associated Protein Promotes Angiogenesis via Signal Transducer and Activator of Transcription 3 in Endothelial Cells
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Yes 相关蛋白通过内皮细胞中的信号转导器和转录激活剂 3 促进血管生成。
DOI：
10.1161/circresaha.117.311950
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发表时间：
2018-02-16
影响因子：
20.1
通讯作者：
Ai, Ding
中科院分区：
文献类型：
--
作者：
He, Jinlong;Bao, Qiankun;Ai, Ding
理论基础：血管生成是一个调节内皮细胞(EC)功能的复杂过程。越来越多的证据支持YAP(Yes-Associated Protein，YAP)在调节内皮细胞血管生成活性中起重要作用。目的：本研究的目的是明确EC YAP对血管生成的影响及其机制。方法与结果：血管内皮细胞生长因子使ECs中YAP的磷酸化时间和剂量依赖地减少，并增加其核聚集。利用Tie2Cre介导的YAP转基因小鼠，我们发现YAP促进了出生后视网膜和肿瘤组织的血管生成。质谱仪显示信号转导和转录激活因子3(STAT3)是YAP在内皮细胞中潜在的结合伙伴。免疫印迹和免疫沉淀分析表明，YAP通过阻断染色体维持性1介导的STAT3核输出而延长了白介素6诱导的STAT3核聚集，而不影响其磷酸化。此外，YAP过表达可增强STAT3诱导的血管生成素-2的表达。结论：在Tie2Cre介导的YAP转基因小鼠中，选择性的STAT3抑制剂或Angiopoietin-2阻断可部分抑制视网膜血管生成。结论：YAP结合使STAT3在细胞核内持续存在，增强后者的转录活性，并通过调节Angiopoietin-2促进血管生成。
Rationale: Angiogenesis is a complex process regulating endothelial cell (EC) functions. Emerging lines of evidence support that YAP (Yes-associated protein) plays an important role in regulating the angiogenic activity of ECs.Objective: The objective of this study was to specify the effect of EC YAP on angiogenesis and its underlying mechanisms.Method and Results: In ECs, vascular endothelial growth factor reduced YAP phosphorylation time and dose dependently and increased its nuclear accumulation. Using Tie2Cre-mediated YAP transgenic mice, we found that YAP promoted angiogenesis in the postnatal retina and tumor tissues. Mass spectrometry revealed signal transducer and activator of transcription 3 (STAT3) as a potential binding partner of YAP in ECs. Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6-induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1-mediated STAT3 nuclear export without affecting its phosphorylation. Moreover, angiopoietin-2 expression induced by STAT3 was enhanced by YAP overexpression in ECs. Finally, a selective STAT3 inhibitor or angiopoietin-2 blockage partly attenuated retinal angiogenesis in Tie2Cre-mediated YAP transgenic mice.Conclusions: YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2.