title: Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways.
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.
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Zhenqian
authors.initials: Z
authors.lastname: Hu
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Han
authors.forename: Beibei
authors.initials: B
authors.lastname: Jiang
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.forename: Chenyang
authors.initials: C
authors.lastname: Geng
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Huo
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Jincai
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005089:Exocytosis; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D020302:Weibel-Palade Bodies / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D019007:P-Selectin; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma; D002118:Calcium