Hypertensive stretch regulates endothelial exocytosis of WeibeI-Palade bodies through VEGF receptor 2 signaling pathways  

作　　者：Yan Xiong Zhenqian Hu Xiaofan Han Beibei Jiang Rongli Zhan Xiaoyu Zhang Yao Lu Chenyang Geng Wei Li Yulong He Yingqing Huo Masabuml Shlbuya Jincai Luo 

机构地区：[1]Laboratory of Vascular Biology [2]Non-human Primate Research Center, Institute of Molecular Medicine, Peking University, Bei- jing 100871, China [3]people's Hospital, Peking University, Beij'ing 100871, China [4]Laboratory of Vascular and Cancer Biology, Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215325, China, [5]Institute of Physiology and Medicine, Jobu University, Takasaki, Japan

出　　处：《Cell Research》2013年第6期820-834,共15页细胞研究（英文版）

基　　金：We thank Drs Quan Chen, Mian Long, Chunyang Xiong and Zhihong Li for helpful discussions on the project. We thank Drs Peace Cheng, Nanping Wang, Xiaocheng Gu and Iain C Bruce for reading the manuscript and offering valuable comments. We also thank Dr Xiuqin Zhang and Ms Ning Hou for technical assistance. Jincai Luo is supported by grants from the National Basic Research Program of China （2012CB945100） and the National Natural Science Foundation of China （81170098 and 81070115）. Yulong He is supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

摘　　要：Regulated endothelial exocytosis of WeibelPalade bodies （WPBs）, the first stage in leukocyte trafficking, plays a pivotal role in inflammation and injury. Acute mechanical stretch has been closely associated with vascular inflamma tion, although the precise mechanism is unknown. Here, we show that hypertensive stretch regulates the exocytosis of WPBs of endothelial cells （ECs） through VEGF receptor 2 （VEGFR2） signaling pathways. Stretch triggers a rapid release （within minutes） of von Willebrand factor and interleukin8 from WPBs in cultured human ECs, promoting the interaction between leukocytes and ECs through the translocation of Pselectin to the cell membrane. We further show that hypertensive stretch significantly induces Pselectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo. Stretchinduced endothelial exocytosis is mediated via a VEGFR2/PLCy1/caicium pathway. Interestingly, stretch also induces a negative feedback via a VEGFR2/Akt/nitric oxide pathway. Such dual effects are confirmed using pharmacological and genetic approaches in carotid artery segments, as well as in acute hypertensive mouse models. These studies reveal mechanical stretch as a potent agonist for endothelial exocytosis, which is modulated by VEGFR2 signaling. Thus, VEGFR2 signaling pathways may represent novel therapeutic tar gets in limiting hypertensive stretchrelated inflammation.Regulated endothelial exocytosis of WeibelPalade bodies （WPBs）, the first stage in leukocyte trafficking, plays a pivotal role in inflammation and injury. Acute mechanical stretch has been closely associated with vascular inflamma tion, although the precise mechanism is unknown. Here, we show that hypertensive stretch regulates the exocytosis of WPBs of endothelial cells （ECs） through VEGF receptor 2 （VEGFR2） signaling pathways. Stretch triggers a rapid release （within minutes） of von Willebrand factor and interleukin8 from WPBs in cultured human ECs, promoting the interaction between leukocytes and ECs through the translocation of Pselectin to the cell membrane. We further show that hypertensive stretch significantly induces Pselectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo. Stretchinduced endothelial exocytosis is mediated via a VEGFR2/PLCy1/caicium pathway. Interestingly, stretch also induces a negative feedback via a VEGFR2/Akt/nitric oxide pathway. Such dual effects are confirmed using pharmacological and genetic approaches in carotid artery segments, as well as in acute hypertensive mouse models. These studies reveal mechanical stretch as a potent agonist for endothelial exocytosis, which is modulated by VEGFR2 signaling. Thus, VEGFR2 signaling pathways may represent novel therapeutic tar gets in limiting hypertensive stretchrelated inflammation.

关 键 词：endothelial cells STRETCH VEGF receptor exocytosis of Weibel-Palade bodies 

分 类 号：Q492[生物学—生理学] Q25