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

Background-Peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists are commonly used to treat diabetes, although their PPAR gamma-dependent effects transcend their role as insulin sensitizers. Thiazolidinediones lower blood pressure (BP) in diabetic patients, whereas results from conventional/tissue-specific PPAR gamma experimental models suggest an important pleiotropic role for PPAR gamma in BP control. Little evidence is available on the molecular mechanisms underlying the role of vascular smooth muscle cell-specific PPAR gamma in basal vascular tone. Methods and Results-We show that vascular smooth muscle cell-selective deletion of PPAR gamma 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 PPAR gamma 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 beta 2-AdR responsiveness, we found that the absence of PPAR gamma in vascular smooth muscle cells increased beta 2-AdR expression, possibly leading to the hypotensive phenotype during the rest phase. Conclusion-These data uncovered the beta 2-AdR as a novel target of PPAR gamma transcriptional repression in vascular smooth muscle cells and indicate that PPAR gamma regulation of beta 2-adrenergic signaling is important in the modulation of BP. (Circulation. 2009;119:2161-2169.)