Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

Abstract

Aim: To examine the contribution of vascular membrane-associated prostaglandin E2 synthase-1 (mPGES-1) to acute blood pressure homeostasis. Methods: Angiotensin II (AngII, 75 pmol·kg -1 ·min -1 ) was continuously infused via the jugular vein into wild-type and mPGES-1 -/-mice for 30 min, and blood pressure was measured by carotid arterial catheterization. RT-PCR and immunohistochemistry were performed to detect the expression and localization of mPGES-1 in the mouse arterial vessels. Mesenteric arteries were dissected from mice of both genotypes to study vessel tension and measure vascular PGE2 levels. Results: Wild-type and mPGES-1 -/-mice showed similar blood pressure levels at baseline, and the acute intravenous infusion of AngII caused a greater increase in mean arterial pressure in the mPGES-1 -/-group, with a similar diuretic and natriuretic response in both groups. mPGES-1 was constitutively expressed in the aortic and mesenteric arteries and vascular smooth muscle cells of wild-type mice. Strong staining was detected in the smooth muscle layer of arterial vessels. Ex vivo treatment of mesenteric arteries with AngII produced more vasodilatory PGE2 in wild-type than in mPGES-1 -/-mice. In vitro tension assays further revealed that the mesenteric arteries of mPGES-1 -/-mice exhibited a greater vasopressor response to AngII than those arteries of wild-type mice. Conclusion: Vascular mPGES-1 acts as an important tonic vasodilator, contributing to acute blood pressure regulation.Keywords: prostaglandin E2; membrane-associated prostaglandin E2 synthase-1; angiotensin II; blood pressure; resistant vessel Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1284Sinica ( -1292 doi: 10.1038/aps.2010 published online 27 Sep 2010 Original Article * To whom correspondence should be addressed. [14] , but its relative contribution to PGE2 generation in vivo remains largely uncharacterized. The third form of PGES (cPGES) was originally isolated from cytoplasmic extracts and is expressed ubiquitously in a constitutive housekeeping manner and functionally coupled with COX-1 to generate physiological PGE2 [15,16] . A large body of evidence demonstrates that PGE2 exerts both vasoconstrictive and vasodilatory actions via its four G-protein coupled receptors: EP1, EP2, EP3, and EP4 [17,18] . However, the net effect of PGE2 appears to be the reduction of blood pressure [19][20][21] . This finding is consistent with clinical observations that nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX inhibitors, can cause hypertension [22][23][24] . Similarly, COX-2 inhibitors increase blood pressure in both animals and patients [25][26][27][28] , which suggests that COX-2-derived prostaglandins are predominantly the vasodilators. Since mPGES-1 is generally believed to be coupled with COX-2 to mediate PGE2 biosynthesis, mPGES-1-derived PGE2 may also exert a vasodepressor effect in vivo. Indeed, recent studies found that deletion of the mPGES-1 gene caused a hypersensitive phenotype in response to chronic salt loading and angiotens...

Targeted Disruption of the Prostaglandin E 2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

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Regulation and function of renal medullary cyclooxygenase-2 during high salt loading

“…Zhang et al further confirmed the vasodilatory and antihypertensive role of mPGES-1 during acute ANG II infusion. (75) Salazar FJ et al employed a selective mPGES-1 inhibitor (PF-458) to study the renal effects of prolonged mPGES-1 inhibition. (76) The results showed mPGES-1 inhibition reduced renal blood flow (RBF) in dogs with low salt intake (LSI), but did not alter glomerular filtration rate (GFR) or renal hemodynamics.…”

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE2 Receptors in Cardiovascular Health and Diseases

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