Endothelial cell prostaglandin E2 receptor EP4 is essential for blood pressure homeostasis.
Endothelial cell prostaglandin E2 receptor EP4 is essential for blood pressure homeostasis.
复制标题
内皮细胞前列腺素 E2 受体 EP4 对于血压稳态至关重要。
DOI：
10.1172/jci.insight.138505
复制
发表时间：
2020
期刊：
影响因子：
8
通讯作者：
Guan Youfei
中科院分区：
文献类型：
--
作者：
Xu Hu;Fang Bingying;Du Shengnan;Wang Sailun;Li Qingwei;Jia Xiao;Bao Chengzhen;Ye Lan;Sui Xue;Qian Lei;Luan Zhilin;Yang Guangrui;Zheng Feng;Wang Nanping;Chen Lihong;Zhang Xiaoyan;Guan Youfei
前列腺素E2及其同源的EP 1 -4受体在血压调节中起重要作用。在此，我们表明，内皮细胞特异性（EC-特异性）EP 4基因敲除小鼠（EC-EP 4-/-）表现出升高，而EC-特异性EP 4过表达小鼠（EC-hEP 4 OE）显示降低，与对照小鼠相比，在基础和高盐饮食喂养条件下的BP水平。用内皮型一氧化氮合酶（eNOS）的竞争性抑制剂l-NG-硝基-l-精氨酸甲酯（l-NAME）治疗可完全消除血压的改变。EC-EP 4-/-小鼠的肠系膜动脉显示对血管紧张素II的血管收缩反应增加和对乙酰胆碱的血管舒张反应减少，这两者都被L-NAME消除。此外，EP 4激活显着降低高血压大鼠的血压水平。机制上，EP 4缺失通过减少eNOS在Ser 1177的磷酸化而显著降低血管中的NO含量。EP 4主要通过AMPK途径促进内皮细胞NO的产生。总的来说，我们的研究结果表明，内皮EP 4是必不可少的血压稳态。
Prostaglandin E2 and its cognate EP1–4 receptors play important roles in blood pressure (BP) regulation. Herein, we show that endothelial cell–specific (EC-specific) EP4 gene–knockout mice (EC-EP4–/–) exhibited elevated, while EC-specific EP4-overexpression mice (EC-hEP4OE) displayed reduced, BP levels compared with the control mice under both basal and high-salt diet–fed conditions. The altered BP was completely abolished by treatment with l–NG-nitro-l-arginine methyl ester (l-NAME), a competitive inhibitor of endothelial nitric oxide synthase (eNOS). The mesenteric arteries of the EC-EP4–/– mice showed increased vasoconstrictive response to angiotensin II and reduced vasorelaxant response to acetylcholine, both of which were eliminated by l-NAME. Furthermore, EP4 activation significantly reduced BP levels in hypertensive rats. Mechanistically, EP4 deletion markedly decreased NO contents in blood vessels via reducing eNOS phosphorylation at Ser1177. EP4 enhanced NO production mainly through the AMPK pathway in cultured ECs. Collectively, our findings demonstrate that endothelial EP4 is essential for BP homeostasis.