Published Online
on April 13, 2009

A more recent version of this article appeared on April 28, 2009

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Submitted on August 18, 2008
Accepted on February 17, 2009

Vascular Smooth Muscle Cell–Selective Peroxisome Proliferator–Activated Receptor- Deletion Leads to Hypotension

Lin Chang MD, PhD, Luis Villacorta PhD, Jifeng Zhang MS, Minerva T. Garcia-Barrio PhD, Kun Yang MS, Milton Hamblin PhD, Steven E. Whitesall BS, Louis G. D'Alecy DMD, PhD, and Y. Eugene Chen MD, PhD^*

From the Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor (L.C., L.V., J.Z., K.Y., M.H., Y.E.C.); Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Ga (M.T.G.-B); and Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor (S.E.W., L.G.D.).

^* To whom correspondence should be addressed. E-mail: echenum{at}umich.edu.

Background—Peroxisome proliferator–activated receptor- (PPAR) agonists are commonly used to treat diabetes, although their PPAR-dependent effects transcend their role as insulin sensitizers. Thiazolidinediones lower blood pressure (BP) in diabetic patients, whereas results from conventional/tissue-specific PPAR experimental models suggest an important pleiotropic role for PPAR in BP control. Little evidence is available on the molecular mechanisms underlying the role of vascular smooth muscle cell–specific PPAR in basal vascular tone.

Methods and Results—We show that vascular smooth muscle cell–selective deletion of PPAR impairs vasoactivity with an overall reduction in BP. Aortic contraction in response to norepinephrine is reduced and vasorelaxation is enhanced in response to -adrenergic receptor (-AdR) agonists in vitro. Similarly, vascular smooth muscle cell–selective PPAR knockout mice display a biphasic response to norepinephrine in BP, reversible on administration of -AdR blocker, and enhanced BP reduction on treatment with -AdR agonists. Consistent with enhanced 2-AdR responsiveness, we found that the absence of PPAR in vascular smooth muscle cells increased 2-AdR expression, possibly leading to the hypotensive phenotype during the rest phase.

Conclusion—These data uncovered the 2-AdR as a novel target of PPAR transcriptional repression in vascular smooth muscle cells and indicate that PPAR regulation of 2-adrenergic signaling is important in the modulation of BP.

Key words: diabetes mellitus • hypertension • lipids • obesity

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