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De Silva TM, Modrick ML, Ketsawatsomkron P, et al. Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation. Hypertension. 2014;64(5):1088-93doi: 10.1161/HYPERTENSIONAHA.114.03935.
De Silva, T. M., Modrick, M. L., Ketsawatsomkron, P., Lynch, C., Chu, Y., Pelham, C. J., Sigmund, C. D., & Faraci, F. M. (2014). Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation. Hypertension (Dallas, Tex. : 1979), 64(5), 1088-93. https://doi.org/10.1161/HYPERTENSIONAHA.114.03935
De Silva, T Michael, et al. "Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation." Hypertension (Dallas, Tex. : 1979) vol. 64,5 (2014): 1088-93. doi: https://doi.org/10.1161/HYPERTENSIONAHA.114.03935
De Silva TM, Modrick ML, Ketsawatsomkron P, Lynch C, Chu Y, Pelham CJ, Sigmund CD, Faraci FM. Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation. Hypertension. 2014 Nov;64(5):1088-93. doi: 10.1161/HYPERTENSIONAHA.114.03935. Epub 2014 Sep 02. PMID: 25185134; PMCID: PMC4192060.
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Hypertension. 2014 Nov;64(5):1088-93. doi: 10.1161/HYPERTENSIONAHA.114.03935. Epub 2014 Sep 02.

Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation.

Hypertension (Dallas, Tex. : 1979)

T Michael De Silva, Mary L Modrick, Pimonrat Ketsawatsomkron, Cynthia Lynch, Yi Chu, Christopher J Pelham, Curt D Sigmund, Frank M Faraci

Affiliations

  1. From the Department of Internal Medicine (T.M.D.S., M.L.M., C.L., Y.C., C.D.S., F.M.F.) and Department of Pharmacology (P.K., C.J.P., C.D.S., F.M.F.), Francois M. Abboud Cardiovascular Center, Carver College of Medicine, University of Iowa; and Iowa City Veterans Affairs Healthcare System (F.M.F.).

PMID: 25185134 PMCID: PMC4192060 DOI: 10.1161/HYPERTENSIONAHA.114.03935

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.

© 2014 American Heart Association, Inc.

Keywords: cerebral arteries; microcirculation; nitric oxide; small vessel disease

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