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: Satoshi Shirao, Hiroshi Yoneda, Mizuya Shinoyama, Kazutaka Sugimoto, Hiroyasu Koizumi, Hideyuki Ishihara, Fumiaki Oka, Hirokazu Sadahiro, Sadahiro Nomura, Masami Fujii, Masakatsu Tamechika, Yoshiteru Kagawa, Yuji Owada, Michiyasu Suzuki
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 35 Issue 5 Pg. 835-42 (May 2015) ISSN: 1559-7016 [Electronic] United States
• PMID: 25605290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Antihypertensive Agents
• Dietary Fats
• Membrane Proteins
• Pyridines
• beta-Cyclodextrins
• flotillins
• sphingosine phosphorylcholine
• Phosphorylcholine
• Y 27632
• Cholesterol
• rho-Associated Kinases
• Sphingosine

Topics

• Amides (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Basilar Artery (metabolism, pathology, physiopathology)
• Carotid Artery, Internal (metabolism, pathology, physiopathology)
• Cholesterol (metabolism, pharmacology)
• Dietary Fats (adverse effects, pharmacology)
• Male
• Membrane Microdomains (metabolism, pathology)
• Membrane Proteins (metabolism)
• Muscle Contraction
• Muscle, Smooth, Vascular (metabolism, pathology, physiopathology)
• Phosphorylcholine (analogs & derivatives, metabolism, pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Sphingosine (analogs & derivatives, metabolism, pharmacology)
• Vasospasm, Intracranial (chemically induced, metabolism, pathology, physiopathology)
• beta-Cyclodextrins (pharmacology)
• rho-Associated Kinases (metabolism)