Faculty Collaboration Database

Interference with PPARgamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling. Hypertension 2008 Apr;51(4):867-71

Date

02/21/2008

Pubmed ID

18285614

Pubmed Central ID

PMC2408877

DOI

10.1161/HYPERTENSIONAHA.107.103648

Scopus ID

2-s2.0-42049101837 (requires institutional sign-in at Scopus site)   102 Citations

Abstract

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.

Author List

Beyer AM, Baumbach GL, Halabi CM, Modrick ML, Lynch CM, Gerhold TD, Ghoneim SM, de Lange WJ, Keen HL, Tsai YS, Maeda N, Sigmund CD, Faraci FM

Authors

Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylcholine
Animals
Aorta
Arterioles
Cerebrovascular Circulation
Dinoprost
Endothelin-1
Female
Gene Expression Profiling
Genes, Dominant
Hypertension
Hypertrophy
Male
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
PPAR gamma
Serotonin
Serotonin Agents
Signal Transduction
Vasodilator Agents