title: A novel trigger for cholesterol-dependent smooth muscle contraction mediated by the sphingosylphosphorylcholine-Rho-kinase pathway in the rat basilar artery: a mechanistic role for lipid rafts.
abstract: Hyperlipidemia is a risk factor for abnormal cerebrovascular events. Rafts are cholesterol-enriched membrane microdomains that influence signal transduction. We previously showed that Rho-kinase-mediated Ca(2+) sensitization of vascular smooth muscle (VSM) induced by sphingosylphosphorylcholine (SPC) has a pivotal role in cerebral vasospasm. The goals of the study were to show SPC-Rho-kinase-mediated VSM contraction in vivo and to link this effect to cholesterol and rafts. The SPC-induced VSM contraction measured using a cranial window model was reversed by Y-27632, a Rho-kinase inhibitor, in rats fed a control diet. The extent of SPC-induced contraction correlated with serum total cholesterol. Total cholesterol levels in the internal carotid artery (ICA) were significantly higher in rats fed a cholesterol diet compared with a control diet or a β-cyclodextrin diet, which depletes VSM cholesterol. Western blotting and real-time PCR revealed increases in flotillin-1, a raft marker, and flotillin-1 mRNA in the ICA in rats fed a cholesterol diet, but not in rats fed the β-cyclodextrin diet. Depletion of cholesterol decreased rafts in VSM cells, and prevention of an increase in cholesterol by β-cyclodextrin inhibited SPC-induced contraction in a cranial window model. These results indicate that cholesterol potentiates SPC-Rho-kinase-mediated contractions of importance in cerebral vasospasm and are compatible with a role for rafts in this process.
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shirao
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoneda
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Mizuya
authors.initials: M
authors.lastname: Shinoyama
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Koizumi
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ishihara
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Oka
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sadahiro
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Nomura
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Organ Anatomy, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Tamechika
authors.affiliation: Department of Organ Anatomy, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Kagawa
authors.affiliation: Department of Organ Anatomy, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Owada
authors.affiliation: Department of Neurosurgery and Clinical Neuroscience, Yamaguchi University School of Medicine, Ube, Japan.
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001488:Basilar Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002343:Carotid Artery, Internal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D020301:Vasospasm, Intracranial / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D047392:beta-Cyclodextrins / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D004041:Dietary Fats; D008565:Membrane Proteins; D011725:Pyridines; D047392:beta-Cyclodextrins; C106354:flotillins; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; C108830:Y 27632; D002784:Cholesterol; D054460:rho-Associated Kinases; D013110:Sphingosine