EP3 (E-Prostanoid 3) Receptor Mediates Impaired Vasodilation in a Mouse Model of Salt-Sensitive Hypertension

Author:

Wu Jing1ORCID,Fang Shi12ORCID,Lu Ko-Ting1,Wackman Kelsey1,Schwartzman Michal L.3,Dikalov Sergey I.4ORCID,Grobe Justin L.1ORCID,Sigmund Curt D.1ORCID

Affiliation:

1. From the Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (J.W., S.F., K.-T.L., K.W., J.L.G., C.D.S.)

2. Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa (S.F.)

3. Department of Pharmacology, New York Medical College School of Medicine, Valhalla (M.L.S.)

4. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (S.D.).

Abstract

We previously showed that impaired vasodilation in systemic and renal vessels contributes to salt-sensitive hypertension in a mouse model of impaired PPARγ (peroxisome proliferator-activated receptor gamma) function. We determined the mechanisms mediating impaired salt-induced vasodilation and whether improved vasodilation attenuates augmented hypertension in response to salt. Mice selectively expressing a PPARγ dominant negative mutation in vascular smooth muscle (S-P467L) exhibited salt-sensitive hypertension and severely impaired vasodilation in systemic and renal vessels. High-salt diet–fed S-P467L and control mice displayed comparable levels of renal oxidative stress markers. Preincubation with Tempol, a superoxide dismutase mimetic, or calphostin C, a PKC (protein kinase C) inhibitor, failed to improve salt-induced impairment of vasodilation in S-P467L mice, arguing against a role of oxidative stress or PKC activity. Inhibition of Rho kinase partially rescued impaired vasodilation in high-salt diet–fed S-P467L mice suggesting a contribution of the Ras homolog family member A (RhoA)/Rho kinase pathway. High-salt diet selectively increased synthesis of PGE2 (prostaglandin E2) in S-P467L aorta. Expression of EP3 (E-prostanoid 3) receptor mRNA was increased in aorta from chow-fed and high salt–fed S-P467L mice. Pharmacological inhibition of COX (cyclooxygenase) 2 or blockade of EP3 completely normalized the impaired vasodilation, and EP3 antagonism induced larger decreases in systolic blood pressure in high-salt diet–fed S-P467L mice. In conclusion, interference with PPARγ in vascular smooth muscle causes activation of the PGE2/EP3 signaling pathway in systemic and renal vasculature resulting in salt-induced impairment of vasodilation and salt-sensitive hypertension. PGE2/EP3 axis maybe a druggable target to prevent salt-sensitive hypertension in chronic conditions associated with decreased PPARγ activity.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

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