Inactivation of the E-Prostanoid 3 Receptor Attenuates the Angiotensin II Pressor Response via Decreasing Arterial Contractility

Abstract

Objective— The present studies aimed at elucidating the role of prostaglandin E 2 receptor subtype 3 (E-prostanoid [EP] 3) in regulating blood pressure. Methods and Results— 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. Conclusion— 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.