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(Circulation. 2008;117:1065-1074.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Role of Caveolar Compartmentation in Endothelium-Derived Hyperpolarizing Factor–Mediated Relaxation

Ca²⁺ Signals and Gap Junction Function Are Regulated by Caveolin in Endothelial Cells

J. Saliez, BSc; C. Bouzin, PhD^*; G. Rath, PhD^*; P. Ghisdal, PhD; F. Desjardins, PhD; R. Rezzani, PhD; L.F. Rodella, PhD; J. Vriens, PhD; B. Nilius, MD, PhD; O. Feron, PhD; J-L. Balligand, MD, PhD; C. Dessy, PhD

From the Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Medical School, Brussels, Belgium (J.S., C.B., G.R., P.G., F.D., O.F., J-L.B., C.D.); Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (R.R., L.F.R.); and KU Leuven, Department of Molecular Cell Biology, Division of Physiology, Campus Gasthuisberg, Leuven, Belgium (J.V., B.N.).

Correspondence to Chantal Dessy, Department of Medicine, Unit of Pharmacology and Therapeutics, FATH 5349, Université catholique de Louvain, 52 Avenue Mounier, B-1200 Brussels, Belgium. E-mail chantal.dessy{at}uclouvain.be

Received August 2, 2007; accepted December 14, 2007.

Background— In endothelial cells, caveolin-1, the structural protein of caveolae, acts as a scaffolding protein to cluster lipids and signaling molecules within caveolae and, in some instances, regulates the activity of proteins targeted to caveolae. Specifically, different putative mediators of the endothelium-derived hyperpolarizing factor (EDHF)–mediated relaxation are located in caveolae and/or regulated by the structural protein caveolin-1, such as potassium channels, calcium regulatory proteins, and connexin 43, a molecular component of gap junctions.

Methods and Results— Comparing relaxation in vessels from caveolin-1 knockout mice and their wild-type littermates, we observed a complete absence of EDHF-mediated vasodilation in isolated mesenteric arteries from caveolin-1 knockout mice. The absence of caveolin-1 is associated with an impairment of calcium homeostasis in endothelial cells, notably, a decreased activity of Ca²⁺-permeable TRPV4 cation channels that participate in nitric oxide– and EDHF-mediated relaxation. Moreover, morphological characterization of caveolin-1 knockout and wild-type arteries showed fewer gap junctions in vessels from knockout animals associated with a lower expression of connexins 37, 40, and 43 and altered myoendothelial communication. Finally, we showed that TRPV4 channels and connexins colocalize with caveolin-1 in the caveolar compartment of the plasma membrane.

Conclusions— We demonstrated that expression of caveolin-1 is required for EDHF-related relaxation by modulating membrane location and activity of TRPV4 channels and connexins, which are both implicated at different steps in the EDHF-signaling pathway.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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