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Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1.

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Author

Summary, in English

The reactivity of the vascular wall to endothelin-1 (ET-1) is influenced by cholesterol, which is of possible importance for the progression of atherosclerosis. To elucidate signaling steps affected, the cholesterol acceptor methyl-ß-cyclodextrin (mßcd, 10 mmol/L) was used to manipulate membrane cholesterol and disrupt caveolae in intact rat arteries. In endothelium-denuded caudal artery, contractile responsiveness to 10 nmol/L ET-1 (mediated by the ETA receptor) was reduced by mßcd and increased by cholesterol. Neither ligand binding nor colocalization of ETA and caveolin-1 was affected by mßcd. Ca2+ inflow via store-operated channels after depletion of intracellular Ca2+ stores was reduced in mßcd-treated caudal arteries, as shown by Mn2+ quench rate and intracellular [Ca2+] response. Expression of TRPC1, 3, and 6 was detected by reverse transcriptase–polymerase chain reaction, and colocalization of TRPC1 with caveolin-1 was reduced by mßcd, as seen by immunofluorescence. Part of the contractile response to ET-1 was inhibited by Ni2+ (0.5 mmol/L) and by a TRPC1 blocking antibody. In the basilar artery, exhibiting less store-operated channel activity than the caudal artery, ET-1–induced contractions were insensitive to the TRPC1 blocking antibody and to mßcd. Increased store-operated channel activity in basilar arteries after organ culture correlated with increased sensitivity of ET-1 contraction to mßcd. These results suggest that cholesterol influences vascular reactivity to ET-1 by affecting the caveolar localization of TRPC1.

Publishing year

2003

Language

English

Pages

839-847

Publication/Series

Circulation Research

Volume

93

Issue

9

Document type

Journal article

Publisher

American Heart Association

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • methyl-ß-cyclodextrin
  • arterial smooth muscle
  • endothelin
  • caveolae
  • store-operated Ca2+ channels

Status

Published

Research group

  • Vascular Physiology
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Clinical and Experimental Allergy Research
  • Neurophysiology

ISBN/ISSN/Other

  • ISSN: 0009-7330