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

• Published in: Circulation (New York, N.Y.) Vol. 119; no. 16; pp. 2161 - 2169
• Main Authors: LIN CHANG, VILLACORTA, Luis, JIFENG ZHANG, GARCIA-BARRIO, Minerva T, KUN YANG, HAMBLIN, Milton, WHITESALL, Steven E, D'ALECY, Louis G, CHEN, Y. Eugene
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 28.04.2009
• Subjects: Animals; Aorta - drug effects; Aorta - physiology; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Blood Pressure - physiology; Blood vessels and receptors; Cardiology. Vascular system; Diabetes Mellitus, Type 2 - drug therapy; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - physiology; Hypotension - chemically induced; Hypotension - genetics; Hypotension - physiopathology; Medical sciences; Mice; Mice, Knockout; Muscle, Smooth, Vascular - physiology; Norepinephrine - pharmacology; PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; Promoter Regions, Genetic - physiology; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Thiazolidinediones - pharmacology; Transcription, Genetic - physiology; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilation - physiology; Vertebrates: cardiovascular system; Endocrinopathy; Hypertension; Obesity; lipids; Diabetes mellitus; Nutrition disorder; Deletion; Smooth muscle; Cardiovascular disease; Nutritional status; Peroxisome proliferator
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.108.815803

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.