Interference with PPARgamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling.
The transcription factor PPARgamma is expressed in endothelium and vascular muscle where it may exert antiinflammatory and antioxidant effects. We tested the hypothesis that PPARgamma plays a protective role in the vasculature by examining vascular structure and function in heterozygous knockin mice expressing the P465L dominant negative mutation in PPARgamma (L/+). In L/+ aorta, responses to the endothelium-dependent agonist acetylcholine (ACh) were not affected, but there was an increase in contraction to serotonin, PGF(2alpha), and endothelin-1. In cerebral blood vessels both in vitro and in vivo, ACh produced dilation that was markedly impaired in L/+ mice. Superoxide levels were elevated in cerebral arterioles from L/+ mice and responses to ACh were restored to normal with a scavenger of superoxide. Diameter of maximally dilated cerebral arterioles was less, whereas wall thickness and cross-sectional area was greater in L/+ mice, indicating cerebral arterioles underwent hypertrophy and remodeling. Thus, interference with PPARgamma signaling produces endothelial dysfunction via a mechanism involving oxidative stress and causes vascular hypertrophy and inward remodeling. These findings indicate that PPARgamma has vascular effects which are particularly profound in the cerebral circulation and provide genetic evidence that PPARgamma plays a critical role in protecting blood vessels.
Beyer
Andreas M
AM
Genetics Graduate Program, Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
Baumbach
Gary L
GL
Halabi
Carmen M
CM
Modrick
Mary L
ML
Lynch
Cynthia M
CM
Gerhold
Thomas D
TD
Ghoneim
Shams M
SM
de Lange
Willem J
WJ
Keen
Henry L
HL
Tsai
Yau-Sheng
YS
Maeda
Nobuyo
N
Sigmund
Curt D
CD
Faraci
Frank M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D015237:Dinoprost / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005799:Genes, Dominant; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology*; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D047495:PPAR gamma; D018490:Serotonin Agents; D014665:Vasodilator Agents; D012701:Serotonin; D015237:Dinoprost; D000109:Acetylcholine