Jinlong He1, Qiankun Bao1, Yan Zhang1, Mingming Liu1, Huizhen Lv1, Yajin Liu1, Liu Yao1, Bochuan Li1, Chenghu Zhang1, Shuang He1, Guijin Zhai1, Yan Zhu1, Xin Liu1, Kai Zhang1, Xiu-Jie Wang1, Ming-Hui Zou1, Yi Zhu1, Ding Ai2. 1. 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.). 2. 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.). edin2000cn@gmail.com.
Abstract
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.
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 YAPtransgenic 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 YAPtransgenic mice. CONCLUSIONS:YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of angiopoietin-2.
Authors: Xiao Jiang; Jiandong Hu; Ziru Wu; Sarah Trusso Cafarello; Mario Di Matteo; Ying Shen; Xue Dong; Heike Adler; Massimiliano Mazzone; Carmen Ruiz de Almodovar; Xiaohong Wang Journal: Front Cell Dev Biol Date: 2021-05-13