Interference with PPAR gamma function in smooth muscle causes vascular dysfunction and hypertension.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that plays a critical role in metabolism. Thiazolidinediones, high-affinity PPARgamma ligands used clinically to treat type II diabetes, have been reported to lower blood pressure and provide other cardiovascular benefits. Some mutations in PPARgamma (PPARG) cause type II diabetes and severe hypertension. Here we tested the hypothesis that PPARgamma in vascular muscle plays a role in the regulation of vascular tone and blood pressure. Transgenic mice expressing dominant-negative mutations in PPARgamma under the control of a smooth-muscle-specific promoter exhibit a loss of responsiveness to nitric oxide and striking alterations in contractility in the aorta, hypertrophy and inward remodeling in the cerebral microcirculation, and systolic hypertension. These results identify PPARgamma as pivotal in vascular muscle as a regulator of vascular structure, vascular function, and blood pressure, potentially explaining some of the cardioprotective effects of thiazolidinediones.
Halabi
Carmen M
CM
Genetics Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Beyer
Andreas M
AM
de Lange
Willem J
WJ
Keen
Henry L
HL
Baumbach
Gary L
GL
Faraci
Frank M
FM
Sigmund
Curt D
CD
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure; D002536:Cerebral Arteries / Q000378:metabolism / Q000503:physiopathology; D002940:Circadian Rhythm; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D013599:Systole; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D047495:PPAR gamma; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D018995:Myosin Heavy Chains; D006152:Cyclic GMP