on May 23, 2002
Arteriosclerosis, Thrombosis, and Vascular Biology. 2002
Published online before print May 23, 2002, doi: 10.1161/01.ATV.0000023438.32585.A1
Published online before print May 23, 2002, doi: 10.1161/01.ATV.0000023438.32585.A1
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Submitted on January 11, 2002
Accepted on April 24, 2002
Cholesterol Depletion Disrupts Caveolae and Differentially Impairs Agonist-Induced Arterial Contraction
Karl Dreja ;
From the Department of Physiological Sciences (K.D., P.H., K.S.), Lund University, Lund, Sweden, and the Department of Medical Physiology (M.V., J.V.) and the Department of Medical Anatomy (J.T.-J.), Panum Institute, University of Copenhagen, Copenhagen, Denmark.
* To whom correspondence should be addressed. E-mail: karl.sward{at}mphy.lu.se.
Objective—This study assessed the role of cholesterol-rich membrane regions, including caveolae, in the regulation of arterial contractility.
Methods and Results—Rat tail artery devoid of endothelium was treated with the cholesterol acceptor methyl-ß-cyclodextrin, and the effects on force and Ca2+ handling were evaluated. In cholesterol-depleted preparations, the force responses to 
1-adrenergic receptors, membrane depolarization, inhibition of myosin light chain phosphatase, and activation of G proteins with a mixture of 20 mmol/L NaF and 60 µmol/L AlCl3 were unaffected. In contrast, responses to 5-hydroxytryptamine (5-HT), vasopressin, and endothelin were reduced by >50%. The rise in global intracellular free Ca2+ concentration in response to 5-HT was attenuated, as was the generation of Ca2+ waves at the cellular level. By electron microscopy, cholesterol depletion was found to disrupt caveolae. The 5-HT response could be restored by exogenous cholesterol, which also restored caveolae. Western blots showed that the levels of 5-HT2A receptor and of caveolin-1 were unaffected by cholesterol extraction. Sucrose gradient centrifugation showed enrichment of 5-HT2A receptors, but not 1-adrenergic receptors, in the caveolin-1--containing fractions, suggesting localization of the former to caveolae.
Conclusions—These results show that a subset of signaling pathways that regulate smooth muscle contraction depends specifically on cholesterol. Furthermore, the cholesterol-dependent step in serotonergic signaling occurs early in the pathway and depends on the integrity of caveolae.
Key words: smooth muscle • caveolae • confocal imaging • 5-hydroxytryptamine • vasopressin • endothelin • microscopy • intracellular calcium
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