Affiliation:
1. From the Department of Physiological Sciences (A.B., M.F.G., K.D., M.A., J.B., P.H., K.S.), Lund University, Sweden, and School of Biomedical Sciences (S.-Z.X., D.J.B.), University of Leeds, UK.
Abstract
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-β-cyclodextrin (mβcd, 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 ET
A
receptor) was reduced by mβcd and increased by cholesterol. Neither ligand binding nor colocalization of ET
A
and caveolin-1 was affected by mβcd. Ca
2+
inflow via store-operated channels after depletion of intracellular Ca
2+
stores was reduced in mβcd-treated caudal arteries, as shown by Mn
2+
quench rate and intracellular [Ca
2+
] 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 mβcd, as seen by immunofluorescence. Part of the contractile response to ET-1 was inhibited by Ni
2+
(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 mβcd. Increased store-operated channel activity in basilar arteries after organ culture correlated with increased sensitivity of ET-1 contraction to mβcd. These results suggest that cholesterol influences vascular reactivity to ET-1 by affecting the caveolar localization of TRPC1.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
182 articles.
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