Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia.
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.
Yagita
Yoshiki
Y
Stroke Division, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. yagita@medone.med.osaka-u.ac.jp
Kitagawa
Kazuo
K
Sasaki
Tsutomu
T
Terasaki
Yasukazu
Y
Todo
Kenichi
K
Omura-Matsuoka
Emi
E
Kaibuchi
Kozo
K
Hori
Masatsugu
M
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
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002148:Calmodulin-Binding Proteins; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D000099291:Adducins; C049347:fasudil