Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways
Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways
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高血压牵张通过 VEGF 受体 2 信号通路调节 Weibel-Palade 小体的内皮胞吐作用
DOI：
10.1038/cr.2013.56
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发表时间：
2013-04
期刊：
影响因子：
44.1
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Xiong Y, Hu Z, Han X, Jiang B, Zhang R, Zhang X;Lu Y, Geng C, Li W, He Y, Huo Y;Shibuya M;Luo J
调节的韦贝尔-帕拉德小体（WPB）的内皮细胞胞吐，白细胞运输的第一阶段，在炎症和损伤中起着关键作用。急性机械牵张与血管炎症密切相关，但确切的机制尚不清楚。在这里，我们表明，高血压牵张调节内皮细胞（ECs）通过VEGF受体2（VEGFR 2）信号通路的WPB的胞吐。牵张触发血管性血友病因子和白细胞介素-8从培养的人EC中的WPB快速释放（在几分钟内），通过P-选择素易位到细胞膜促进白细胞和EC之间的相互作用。我们进一步表明，高血压牵张显着诱导P-选择素易位的完整的EC和增强白细胞粘附在体外和体内。牵张诱导的内皮细胞胞吐作用通过VEGFR 2/PLCγ1/钙通道介导。有趣的是，拉伸也通过VEGFR 2/Akt/一氧化氮途径诱导负反馈。在颈动脉节段以及急性高血压小鼠模型中使用药理学和遗传学方法证实了这种双重作用。这些研究揭示了机械拉伸作为内皮细胞胞吐的有效激动剂，其由VEGFR 2信号传导调节。因此，VEGFR 2信号通路可能代表限制高血压牵张相关炎症的新治疗靶点。
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.
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影响因子：
15.9
作者：
Kobayashi, T;Tahara, Y;Narumiya, S
通讯作者：
Narumiya, S
DOI：
10.1024/0301-1526/a000094
发表时间：
2011-05
期刊：
VASA. Zeitschrift fur Gefasskrankheiten
影响因子：
--
作者：
Z. Xia;H. Yang;H. Qu;W. Cheng;L-X Wang
通讯作者：
Z. Xia;H. Yang;H. Qu;W. Cheng;L-X Wang
影响因子：
6.7
作者：
Napoli, Claudio;Ignarro, Louis J.
通讯作者：
Ignarro, Louis J.
DOI：
10.1161/atvbaha.107.148189
发表时间：
2007-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Hannah Song;A. Mowbray;M. Sykes;H. Jo
通讯作者：
Hannah Song;A. Mowbray;M. Sykes;H. Jo
影响因子：
44.1
作者：
Liao, XD;Wang, XH;Chen, Q
通讯作者：
Chen, Q