Interference with PPARγ signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling

Andreas M. Beyer, Gary L. Baumbach, Carmen M. Halabi, Mary L. Modrick, Cynthia M. Lynch, Thomas D. Gerhold, Shams M. Ghoneim, Willem J. De Lange, Henry L. Keen, Yau Sheng Tsai, Nobuyo Maeda, Curt D. Sigmund, Frank M. Faraci

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

The transcription factor PPARγ is expressed in endothelium and vascular muscle where it may exert antiinflammatory and antioxidant effects. We tested the hypothesis that PPARγ plays a protective role in the vasculature by examining vascular structure and function in heterozygous knockin mice expressing the P465L dominant negative mutation in PPARγ (L/+). In L/+ aorta, responses to the endothelium-dependent agonist acetylcholine (ACh) were not affected, but there was an increase in contraction to serotonin, PGF2α, 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 PPARγ signaling produces endothelial dysfunction via a mechanism involving oxidative stress and causes vascular hypertrophy and inward remodeling. These findings indicate that PPARγ has vascular effects which are particularly profound in the cerebral circulation and provide genetic evidence that PPARγ plays a critical role in protecting blood vessels.

Original languageEnglish
Pages (from-to)867-871
Number of pages5
JournalHypertension
Volume51
Issue number4
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

Keywords

  • Dominant negative
  • Endothelial function
  • Hypertension
  • Hypertrophy
  • Remodeling

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    Beyer, A. M., Baumbach, G. L., Halabi, C. M., Modrick, M. L., Lynch, C. M., Gerhold, T. D., Ghoneim, S. M., De Lange, W. J., Keen, H. L., Tsai, Y. S., Maeda, N., Sigmund, C. D., & Faraci, F. M. (2008). Interference with PPARγ signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling. Hypertension, 51(4), 867-871. https://doi.org/10.1161/HYPERTENSIONAHA.107.103648