From the Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology (J.H., Q.B., M.L., H.L., Y.L., L.Y., B.L., C.Z., G.Z., K.Z., Y.Z., D.A.) and College of Optometry and Ophthalmology, Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute (Y.Z.), Tianjin Medical University, China; Tianjin Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine (S.H., Y.Z.); Key Laboratory of Network Genetics, Collaborative Innovation Center for Cardiovascular Disorders, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing (X.L., X.-J.W.); Center for Molecular and Translational Medicine, Georgia State University, Atlanta (M.-H.Z.); and Tianjin Key Laboratory of Metabolic Diseases, China (Y.Z., D.A.).
Circ Res. 2018 Feb 16;122(4):591-605. doi: 10.1161/CIRCRESAHA.117.311950. Epub 2018 Jan 3.
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.
The objective of this study was to specify the effect of EC YAP on angiogenesis and its underlying mechanisms.
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.
YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2.
血管生成是调节内皮细胞（EC）功能的一个复杂过程。越来越多的证据表明，Yes 相关蛋白（YAP）在调节 EC 的血管生成活性方面起着重要作用。
本研究旨在明确 EC YAP 对血管生成的影响及其潜在机制。
在 EC 中，血管内皮生长因子（VEGF）呈时间和剂量依赖性地降低 YAP 磷酸化，增加其核积累。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。质谱分析显示信号转导和转录激活因子 3（STAT3）是 EC 中 YAP 的潜在结合伴侣。Western blot 和免疫沉淀实验表明，YAP 通过阻断染色体维持蛋白 1 介导的 STAT3 核输出，与 YAP 结合延长了白细胞介素 6 诱导的 STAT3 核积累，而不影响其磷酸化。此外，在 EC 中过表达 YAP 增强了 STAT3 诱导的血管生成素 2 表达。最后，选择性 STAT3 抑制剂或血管生成素 2 阻断部分减轻了 Tie2Cre 介导的 YAP 转基因小鼠的视网膜血管生成。
YAP 与 STAT3 结合，将其维持在核内，增强后者的转录活性，并通过调节血管生成素 2 促进血管生成。
