title: Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia.
abstract: Microcirculatory disturbances contribute to the expansion of infarct lesions after focal cerebral ischemia. Recently, it was shown that Rho-kinase involves in endothelial dysfunction via down-regulation of endothelial nitric oxide synthase function in a rodent stroke model. However, it is not clear whether endothelial Rho-kinase is activated in vivo or Rho-kinase activation contributes to microcirculatory disturbances after cerebral ischemia. In this study, we assessed the temporal and spatial profiles of Rho-kianse activity and the effect of the Rho-kinase inhibitor fasudil on microcirculatory disturbances in the focal brain ischemia. Rho-kinase activation was evaluated by analyzing the phosphorylation of adducin, a substrate of Rho-kinase, by immunohistochemistry. Staining for p-adducin was found in endothelia in the ischemic area 6 hr after induction of ischemia. Microcirculatory disturbances and increased endothelial cell staining for von Willebrand factor (vWF) were observed in the same area. Postischemic treatment with fasudil suppressed endothelial Rho-kinase activation, preserved microcirculation, and inhibited endothelial cell vWF staining. These effects resulted in inhibition of infarct expansion and improvement of neurologic deficits. These findings indicate that Rho-kinase is activated in the endothelial cells and contributes to microcirculatory disturbances in cerebral ischemia. The vascular protective effect of Rho-kinase inhibitors may be useful in the treatment of the acute phase of ischemic stroke.
authors.affiliation: Stroke Division, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. yagita@medone.med.osaka-u.ac.jp
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yagita
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Terasaki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Todo
authors.forename: Emi
authors.initials: E
authors.lastname: Omura-Matsuoka
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D020520:Brain Infarction / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000201:enzymology / Q000473:pathology; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases / Q000378:metabolism*; D000099291:Adducins
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002148:Calmodulin-Binding Proteins; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D000099291:Adducins; C049347:fasudil