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

Abstract

Peroxisome proliferator-activated receptor-γ(PPARγ) agonists are commonly used to treat diabetes, although their PPARγ-dependent effects transcend their role as insulin sensitizers. Thiazolidinediones lower blood pressure (BP) in diabetic patients, whereas results from conventional/tissue-specific PPARγ experimental models suggest an important pleiotropic role for PPARγ in BP control. Little evidence is available on the molecular mechanisms underlying the role of vascular smooth muscle cell-specific PPARγ in basal vascular tone. Methods and Results-We show that vascular smooth muscle cell-selective deletion of PPARγ 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 PPARγ 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 PPARγ 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 PPARγ transcriptional repression in vascular smooth muscle cells and indicate that PPARγ regulation of β2-adrenergic signaling is important in the modulation of BP.(Circulation. 2009;119:2161-2169.)© 2009 American Heart Association, Inc.