Inactivation of the E-prostanoid 3 receptor attenuates the angiotensin II pressor response via decreasing arterial contractility.
Inactivation of the E-prostanoid 3 receptor attenuates the angiotensin II pressor response via decreasing arterial contractility.
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E-前列腺素 3 受体失活通过降低动脉收缩力来减弱血管紧张素 II 升压反应
DOI：
10.1161/atvbaha.112.254052
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发表时间：
2012-12
期刊：
影响因子：
--
通讯作者：
Guan Y
中科院分区：
文献类型：
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作者：
Chen L;Miao Y;Zhang Y;Dou D;Liu L;Tian X;Yang G;Pu D;Zhang X;Kang J;Gao Y;Wang S;Breyer MD;Wang N;Zhu Y;Huang Y;Breyer RM;Guan Y
本研究旨在阐明前列腺素E2（PGE 2）受体亚型3（EP 3）在血压调节中的作用。携带EP 3基因（EP 3 −/−）遗传破坏的小鼠表现出通过尾套和颈动脉导管插入术监测的基线平均动脉压降低。EP 3激动剂M&B28767和硫前列酮诱导的升压反应在EP 3 −/−小鼠中明显减弱，而PGE 2诱导的血压降低在两种基因型中相当。在EP 3 −/−小鼠中，急性或慢性输注血管紧张素II（AngII）的血管加压作用减弱。EP 3 −/−组中AngII诱导的肠系膜动脉血管收缩减少。在野生型小鼠的肠系膜动脉中，AngII诱导的血管收缩被EP 3选择性拮抗剂DG-041或L798106抑制。在EP 3缺陷的肠系膜动脉中，Arhgef-1的表达减弱。EP 3拮抗剂DG-041减少了AngII诱导的离体肠系膜动脉MLC 20和MYPT 1的磷酸化。此外，在血管平滑肌细胞（VSMCs）中，AngII诱导的细胞内Ca 2+升高被EP 3激动剂磺前列酮增强，而DG-041抑制。EP 3受体的激活升高了基线血压，并至少部分地通过增强VSMC中的Ca 2+敏感性和细胞内钙浓度而促成AngII依赖性高血压。选择性靶向EP 3受体可能是治疗高血压的潜在治疗靶点。
The present studies aimed at elucidating the role of prostaglandin E2 (PGE2) receptor subtype 3 (EP3) in regulating blood pressure. Mice bearing a genetic disruption of the EP3 gene (EP3−/−) exhibited reduced baseline mean arterial pressure monitored by both tail-cuff and carotid arterial catheterization. The pressor responses induced by EP3 agonists M&B28767 and sulprostone were markedly attenuated in EP3−/− mice, while the reduction of BP induced by PGE2 was comparable in both genotypes. Vasopressor effect of acute or chronic infusion of angiotensin II (AngII) was attenuated in EP3−/− mice. AngII–induced vasoconstriction in mesenteric arteries decreased in EP3−/− group. In mesenteric arteries from wild type mice, AngII–induced vasoconstriction was inhibited by EP3 selective antagonist DG-041 or L798106. The expression of Arhgef-1 is attenuated in EP3 deficient mesenteric arteries. EP3 antagonist DG-041 diminished AngII-induced phosphorylation of MLC20 and MYPT1 in isolated mesenteric arteries. Furthermore, in vascular smooth muscle cells (VSMCs), AngII induced intracellular Ca2+ increase was potentiated by EP3 agonist sulprostone, while inhibited by DG-041. Activation of the EP3 receptor raises baseline blood pressure and contributes to AngII-dependent hypertension at least partially via enhancing Ca2+ sensitivity and intracellular calcium concentration in VSMCs. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension.