Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways |
| |
Authors: | Yan Xiong Zhenqian Hu Xiaofan Han Beibei Jiang Rongli Zhang Xiaoyu Zhang Yao Lu Chenyang Geng Wei Li Yulong He Yingqing Huo Masabumi Shibuya Jincai Luo |
| |
Affiliation: | 1.Laboratory of Vascular Biology, Institute of Molecular Medicine, Peking University, Beijing 100871, China;2.Non-human Primate Research Center, Institute of Molecular Medicine, Peking University, Beijing 100871, China;3.People''s Hospital, Peking University, Beijing 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 |
| |
Abstract: | Regulated endothelial exocytosis of Weibel-Palade 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 inflammation, 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 interleukin-8 from WPBs in cultured human ECs, promoting the interaction between leukocytes and ECs through the translocation of P-selectin to the cell membrane. We further show that hypertensive stretch significantly induces P-selectin translocation of intact ECs and enhances leukocyte adhesion both ex vivo and in vivo. Stretch-induced endothelial exocytosis is mediated via a VEGFR2/PLCγ1/calcium 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 targets in limiting hypertensive stretch-related inflammation. |
| |
Keywords: | endothelial cells stretch VEGF receptor exocytosis of Weibel-Palade bodies |
|
|