Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 35, Issue 5, Pages 835-842Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2014.260
Keywords
Hyperlipidemia; lipid rafts; Rho-kinase; sphingosylphosphorylcholine; vasospasm
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Funding
- Japan Ministry of Education, Culture, Sports, Science, and Technology
- MEXT of Japan [22791346]
- Kanae Foundation for the Promotion of Medical Science
- Mitsubishi Pharma Research Foundation
- [20001008]
- Grants-in-Aid for Scientific Research [24592130, 22791346] Funding Source: KAKEN
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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 Ca2+ 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 beta-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 beta-cyclodextrin diet. Depletion of cholesterol decreased rafts in VSM cells, and prevention of an increase in cholesterol by beta-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.
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