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 E2 (PGE2) receptor subtype 3 (EP3) in regulating blood pressure. Methods and Results 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. Conclusions 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.

Inhibition of miR-200c Restores Endothelial Function in Diabetic Mice Through Suppression of COX-2

“…PGI 2 (assayed in the form of 6-keto PGF 1a ) was also increased by twofold only in the medium. PGE 2 induces vasoconstriction by binding to PGE 2 receptors 1 and 3 (36,37). PGI 2 is reported to induce contraction in aortas of spontaneously hypertensive rats and aged Wistar-Kyoto rats, probably by interacting with TXA 2 receptors (38).…”

PGE2, Kidney Disease, and Cardiovascular Risk

“…116 The role of COX-2 in the inflammatory response is controversial and it appears that timing is everything, with a dual role as a producer of proinflammatory and proresolving mediators in acute inflammation. 117 PGE 2 plays a central role in the nonresolving inflammatory state associated with the formation of atherosclerotic lesions, and all three EP receptors are somehow implicated in the formation and stabilization of the atherosclerotic lesion. In fact, statins protect against thrombotic events by inhibiting COX-2/mPGES1/PGE 2 /EPmediated instability of carotid plaques, and the expression of EP 1 , EP 3 , and EP 4 receptors is reduced by atorvastatin in both the plaques and mononuclear cells of patients with carotid atherosclerosis.…”

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E2 in Conscious Rats

“…In the periphery, the EP4 receptor mediates vasodilation (Hristovska et al, 2007), whereas EP3, and perhaps EP1 and EP2, receptors mediate vasoconstriction (Kennedy et al, 1999;Guan et al, 2007;Chen et al, 2012). It is worth noting that the central EP3 receptor also mediates BP elevation (Ariumi et al, 2002;Zhang et al, 2011).…”