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(Circulation. 2009;119:2161-2169.)
© 2009 American Heart Association, Inc.

Hypertension

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; 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.).

Correspondence to Dr Y. Eugene Chen, University of Michigan Medical Center, 1150 W Medical Center Dr, MSRB III 7301E, Ann Arbor, MI 48105. E-mail echenum{at}umich.edu

Received August 18, 2008; accepted February 17, 2009.

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 β-adrenergic receptor (β-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 β-AdR blocker, and enhanced BP reduction on treatment with β-AdR agonists. Consistent with enhanced β2-AdR responsiveness, we found that the absence of PPAR in vascular smooth muscle cells increased β2-AdR expression, possibly leading to the hypotensive phenotype during the rest phase.

Conclusion— These data uncovered the β2-AdR as a novel target of PPAR transcriptional repression in vascular smooth muscle cells and indicate that PPAR regulation of β2-adrenergic signaling is important in the modulation of BP.

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Clinical Summaries
Circulation 2009 119: 2125-2126. [Extract] [Full Text]