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Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension.

ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists are commonly used to treat diabetes, although their PPARgamma-dependent effects transcend their role as insulin sensitizers. Thiazolidinediones lower blood pressure (BP) in diabetic patients, whereas results from conventional/tissue-specific PPARgamma experimental models suggest an important pleiotropic role for PPARgamma in BP control. Little evidence is available on the molecular mechanisms underlying the role of vascular smooth muscle cell-specific PPARgamma in basal vascular tone.We show that vascular smooth muscle cell-selective deletion of PPARgamma impairs vasoactivity with an overall reduction in BP. Aortic contraction in response to norepinephrine is reduced and vasorelaxation is enhanced in response to beta-adrenergic receptor (beta-AdR) agonists in vitro. Similarly, vascular smooth muscle cell-selective PPARgamma knockout mice display a biphasic response to norepinephrine in BP, reversible on administration of beta-AdR blocker, and enhanced BP reduction on treatment with beta-AdR agonists. Consistent with enhanced beta2-AdR responsiveness, we found that the absence of PPARgamma in vascular smooth muscle cells increased beta2-AdR expression, possibly leading to the hypotensive phenotype during the rest phase.These data uncovered the beta2-AdR as a novel target of PPARgamma transcriptional repression in vascular smooth muscle cells and indicate that PPARgamma regulation of beta2-adrenergic signaling is important in the modulation of BP.

SUBMITTER: Chang L

PROVIDER: S-EPMC2829656 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension.

Chang Lin L Villacorta Luis L Zhang Jifeng J Garcia-Barrio Minerva T MT Yang Kun K Hamblin Milton M Whitesall Steven E SE D'Alecy Louis G LG Chen Y Eugene YE

Circulation 20090413 16

<h4>Background</h4>Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists are commonly used to treat diabetes, although their PPARgamma-dependent effects transcend their role as insulin sensitizers. Thiazolidinediones lower blood pressure (BP) in diabetic patients, whereas results from conventional/tissue-specific PPARgamma experimental models suggest an important pleiotropic role for PPARgamma in BP control. Little evidence is available on the molecular mechanisms underlying the ...[more]

PMID: 19364979

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension.

Publications

Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension.

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