title: Role of peroxisome proliferator-activated receptor-γ in vascular muscle in the cerebral circulation.
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.
authors.affiliation: 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.).
authors.forename: T Michael
authors.initials: TM
authors.lastname: De Silva
authors.affiliation: 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.).
authors.forename: Mary L
authors.initials: ML
authors.lastname: Modrick
authors.affiliation: 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.).
authors.forename: Pimonrat
authors.initials: P
authors.lastname: Ketsawatsomkron
authors.affiliation: 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.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lynch
authors.affiliation: 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.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.affiliation: 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.).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pelham
authors.affiliation: 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.).
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.affiliation: 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.).
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology; D054460:rho-Associated Kinases / Q000502:physiology
chemical_list: D047495:PPAR gamma; D009569:Nitric Oxide; D054460:rho-Associated Kinases
keywords: cerebral arteries; microcirculation; nitric oxide; small vessel disease