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Cholesterol depletion disrupts caveolae and differentially impairs agonist-induced arterial contraction.

Dreja, Karl LU ; Voldstedlund, Marianne; Vinten, Jørgen; Tranum-Jensen, Jørgen; Hellstrand, Per LU and Swärd, Karl LU (2002) In Arteriosclerosis, Thrombosis and Vascular Biology 22(8). p.1267-1272
Abstract
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-beta-cyclodextrin, and the effects on force and Ca2+ handling were evaluated. In cholesterol-depleted preparations, the force responses to alpha1-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 micro mol/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+... (More)
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-beta-cyclodextrin, and the effects on force and Ca2+ handling were evaluated. In cholesterol-depleted preparations, the force responses to alpha1-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 micro mol/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 alpha1-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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5-hydroxytryptamine, intracellular calcium, endothelin, smooth muscle, caveolae
in
Arteriosclerosis, Thrombosis and Vascular Biology
volume
22
issue
8
pages
1267 - 1272
publisher
American Heart Association
external identifiers
  • pmid:12171786
  • wos:000177530500007
  • scopus:0036344517
ISSN
1524-4636
DOI
10.1161/01.ATV.0000023438.32585.A1
language
English
LU publication?
yes
id
c7502464-e7e1-405c-831f-f2f68b018db6 (old id 109885)
date added to LUP
2007-07-11 13:21:23
date last changed
2017-11-05 03:33:22
@article{c7502464-e7e1-405c-831f-f2f68b018db6,
  abstract     = {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-beta-cyclodextrin, and the effects on force and Ca2+ handling were evaluated. In cholesterol-depleted preparations, the force responses to alpha1-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 micro mol/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 alpha1-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.},
  author       = {Dreja, Karl and Voldstedlund, Marianne and Vinten, Jørgen and Tranum-Jensen, Jørgen and Hellstrand, Per and Swärd, Karl},
  issn         = {1524-4636},
  keyword      = {5-hydroxytryptamine,intracellular calcium,endothelin,smooth muscle,caveolae},
  language     = {eng},
  number       = {8},
  pages        = {1267--1272},
  publisher    = {American Heart Association},
  series       = {Arteriosclerosis, Thrombosis and Vascular Biology},
  title        = {Cholesterol depletion disrupts caveolae and differentially impairs agonist-induced arterial contraction.},
  url          = {http://dx.doi.org/10.1161/01.ATV.0000023438.32585.A1},
  volume       = {22},
  year         = {2002},
}