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

Andreas Bergdahl1, Maria F Gomez, Karl Dreja

  • 1Department of Physiological Sciences, Lund University, Lund, Sweden.

Circulation Research
|October 11, 2003
PubMed

Insights

Cholesterol affects vascular reactivity to endothelin-1 by influencing the caveolar localization of TRPC1 channels. This finding is crucial for understanding atherosclerosis progression and potential therapeutic targets.

Area of Science:

  • Cardiovascular Biology
  • Molecular Pharmacology
  • Atherosclerosis Research

Background:

  • Vascular wall reactivity to endothelin-1 (ET-1) is modulated by cholesterol, a factor implicated in atherosclerosis.
  • Understanding the specific signaling pathways affected by cholesterol is essential for elucidating disease mechanisms.

Purpose of the Study:

  • To investigate how manipulating membrane cholesterol levels affects vascular responses to ET-1.
  • To identify the role of caveolae and TRPC1 channels in cholesterol-mediated vascular signaling.

Main Methods:

  • Used methyl-beta-cyclodextrin (mbetacd) to alter membrane cholesterol and disrupt caveolae in rat arteries.
  • Assessed contractile responses to ET-1, ligand binding, and caveolin-1 colocalization.
  • Measured calcium (Ca2+) inflow via store-operated channels using Mn2+ quench rates and intracellular [Ca2+].
  • Analyzed TRPC1, TRPC3, and TRPC6 expression and TRPC1-caveolin-1 colocalization via RT-PCR and immunofluorescence.

Main Results:

  • In endothelium-denuded caudal arteries, mbetacd reduced ET-1 contractions, while cholesterol increased them.
  • Mbetacd decreased Ca2+ inflow via store-operated channels and reduced TRPC1 colocalization with caveolin-1.
  • ET-1 contractions were partially inhibited by Ni2+ and a TRPC1 blocking antibody.
  • Basilar arteries, with less store-operated channel activity, showed insensitivity to mbetacd and TRPC1 antibody, which changed with increased store-operated channel activity.

Conclusions:

  • Cholesterol influences vascular reactivity to ET-1 by modulating the caveolar localization of TRPC1 channels.
  • Store-operated calcium channels and TRPC1 are key players in cholesterol's effect on vascular tone.
  • These findings offer insights into the pathogenesis of atherosclerosis and potential therapeutic strategies targeting vascular cholesterol homeostasis.

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