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Inactivation of the E-prostanoid 3 receptor attenuates the angiotensin II pressor response via decreasing arterial contractility.

ABSTRACT: The present studies aimed at elucidating the role of prostaglandin E(2) receptor subtype 3 (E-prostanoid [EP] 3) in regulating blood pressure.Mice bearing a genetic disruption of the EP3 gene (EP(3)(-/-)) 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, whereas the reduction of blood pressure induced by prostaglandin E(2) was comparable in both genotypes. Vasopressor effect of acute or chronic infusion of angiotensin II (Ang II) was attenuated in EP3(-/-) mice. Ang II-induced vasoconstriction in mesenteric arteries decreased in EP3(-/-) group. In mesenteric arteries from wild-type mice, Ang II-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 Ang II-induced phosphorylation of myosin light chain 20 and myosin phosphatase target subunit 1 in isolated mesenteric arteries. Furthermore, in vascular smooth muscle cells, Ang II-induced intracellular Ca(2+) increase was potentiated by EP3 agonist sulprostone but inhibited by DG-041.Activation of the EP3 receptor raises baseline blood pressure and contributes to Ang II-dependent hypertension at least partially via enhancing Ca(2+) sensitivity and intracellular calcium concentration in vascular smooth muscle cells. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension.

SUBMITTER: Chen L

PROVIDER: S-EPMC3565847 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Inactivation of the E-prostanoid 3 receptor attenuates the angiotensin II pressor response via decreasing arterial contractility.

Chen Lihong L Miao Yifei Y Zhang Yahua Y Dou Dou D Liu Limei L Tian Xiaoyu X Yang Guangrui G Pu Dan D Zhang Xiaoyan X Kang Jihong J Gao Yuansheng Y Wang Shiqiang S Breyer Matthew D MD Wang Nanping N Zhu Yi Y Huang Yu Y Breyer Richard M RM Guan Youfei Y

Arteriosclerosis, thrombosis, and vascular biology 20121011 12

<h4>Objective</h4>The present studies aimed at elucidating the role of prostaglandin E(2) receptor subtype 3 (E-prostanoid [EP] 3) in regulating blood pressure.<h4>Methods and results</h4>Mice bearing a genetic disruption of the EP3 gene (EP(3)(-/-)) 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, whereas the reducti ...[more]

PMID: 23065824

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Project description:BackgroundNew vessel formation plays a pivotal role in the pathogenesis of neovascular-related diseases. Endothelial progenitor cells (EPCs) were found to contribute to neovascular-related diseases and interference with EPC neovascularization may be a novel target for these diseases. Zoledronate (Zol) was reported to exhibit anti-angiogenic effect. Basing on these evidences, we proposed that Zol may affect EPC function to exert novel anti-angiogenic effect. In this study, we therefore investigated the effects of Zol on multiple aspects of EPC function and explored the underlying mechanisms involved.Methodology/principal findingsEPCs were cultured from bone marrow derived mononuclear cells. The potential effects of Zol on Angiotensin II (Ang II)-stimulated EPC proliferation, migration, adhesion, in vitro tube formation were investigated. The results showed that Ang II (1 µM) enhanced EPC migration, adhesion, in vitro tube formation but had no effect on cell proliferation. Zol (75 and 100 µM) inhibited proliferation of EPCs and 50 µM geranylgeranyol (GGOH) could reverse the decrease of EPC proliferation. We found for the first time that Zol (50-100 µM) dose dependently attenuated migration, adhesion, and in vitro tube formation of EPCs stimulated by Ang II. GGOH could reverse the attenuation of EPC function induced by Zol. However, Zol did not induce EPC apoptosis. In addition, the underlying mechanisms were determined. The results revealed that Zol markedly down-regulated active RhoA stimulated by Ang II and inhibited the phosphorylation of Erk1/2 and JNK. Moreover, RhoA silencing resulted in a notable inhibition of EPC in vitro tube formation, suggesting that RhoA suppression played a pivotal role in Zol antiangiogenic effect.Conclusions/significanceThese findings suggested that Zol attenuated the promotion of EPC function stimulated by Ang II and exhibited novel antiangiogenic effect via RhoA and MAPK signaling. Thus, Zol may be served as a novel therapeutic agent for neovascular-related diseases treatment.

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Inactivation of the E-prostanoid 3 receptor attenuates the angiotensin II pressor response via decreasing arterial contractility.

Publications

Inactivation of the E-prostanoid 3 receptor attenuates the angiotensin II pressor response via decreasing arterial contractility.

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