Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation. Hypertension 2014 Nov;64(5):1088-93
Date
09/04/2014Pubmed ID
25185134Pubmed Central ID
PMC4192060DOI
10.1161/HYPERTENSIONAHA.114.03935Scopus ID
2-s2.0-84925770086 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
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.
Author List
De Silva TM, Modrick ML, Ketsawatsomkron P, Lynch C, Chu Y, Pelham CJ, Sigmund CD, Faraci FMAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsArterioles
Cerebrovascular Circulation
Female
Humans
Male
Mice
Mice, Mutant Strains
Mice, Transgenic
Muscle, Smooth, Vascular
Nitric Oxide
PPAR gamma
Signal Transduction
Vasodilation
rho-Associated Kinases
