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


RESULTS
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.


CONCLUSIONS
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.
Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48105, USA.
Lin
L
Chang
Luis
L
Villacorta
Jifeng
J
Zhang
Minerva T
MT
Garcia-Barrio
Kun
K
Yang
Milton
M
Hamblin
Steven E
SE
Whitesall
Louis G
LG
D'Alecy
Y Eugene
YE
Chen
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005786:Gene Expression Regulation / Q000502:physiology; D007022:Hypotension / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D047495:PPAR gamma; D018343:Receptors, Adrenergic, beta-2; D045162:Thiazolidinediones; D014662:Vasoconstrictor Agents; D009638:Norepinephrine