Journal article
Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation
Hypertension (Dallas, Tex. 1979), Vol.64(5), pp.1088-1093
11/2014
DOI: 10.1161/HYPERTENSIONAHA.114.03935
PMCID: PMC4192060
PMID: 25185134
Abstract
Although peroxisome proliferator-activated receptor-γ (PPARγ) is thought to play a protective role in the vasculature, its cell-specific effect, particularly in resistance vessels, is poorly defined. Nitric oxide (NO) plays a major role in vascular biology in the brain. We examined the hypothesis that selective interference with PPARγ in vascular muscle would impair NO-dependent responses and augment vasoconstrictor responses in the cerebral circulation. We studied mice expressing a dominant negative mutation in human PPARγ (P467L) under the control of the smooth muscle myosin heavy chain promoter (S-P467L). In S-P467L mice, dilator responses to exogenously applied or endogenously produced NO were greatly impaired in cerebral arteries in vitro and in small cerebral arterioles in vivo. Select NO-independent responses, including vasodilation to low concentrations of potassium, were also impaired in S-P467L mice. In contrast, increased expression of wild-type PPARγ in smooth muscle had little effect on vasomotor responses. Mechanisms underlying impairment of both NO-dependent and NO-independent vasodilator responses after interference with PPARγ involved Rho kinase with no apparent contribution by oxidative stress-related mechanisms. These findings support the concept that via effects on Rho kinase-dependent signaling, PPARγ in vascular muscle is a major determinant of vascular tone in resistance vessels and, in particular, NO-mediated signaling in cerebral arteries and brain microvessels. Considering the importance of NO and Rho kinase, these findings have implications for regulation of cerebral blood flow and the pathogenesis of large and small vessel disease in brain.
Details
- Title: Subtitle
- Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation
- Creators
- T Michael De Silva - Roy J. and Lucille A. Carver College of MedicineMary L Modrick - Veterans Health AdministrationPimonrat KetsawatsomkronCynthia LynchYi ChuChristopher J PelhamCurt D SigmundFrank M Faraci
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.64(5), pp.1088-1093
- DOI
- 10.1161/HYPERTENSIONAHA.114.03935
- PMID
- 25185134
- PMCID
- PMC4192060
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Grant note
- I01 BX001399 / BLRD VA R01 HL061446 / NHLBI NIH HHS HL-113863 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS R37 HL048058 / NHLBI NIH HHS HL-48058 / NHLBI NIH HHS P01 NS024621 / NINDS NIH HHS R01 HL113863 / NHLBI NIH HHS NS-24621 / NINDS NIH HHS R01 HL048058 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS HL-61446 / NHLBI NIH HHS HL-62984 / NHLBI NIH HHS
- Language
- English
- Date published
- 11/2014
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984303996402771
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