on February 11, 2008
Published online before print February 11, 2008, doi: 10.1161/CIRCULATIONAHA.107.731679
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Submitted on August 2, 2007
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.). * To whom correspondence should be addressed. E-mail: chantal.dessy{at}uclouvain.be.
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.
Accepted on December 14, 2007
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,
Key words: calcium • endothelium • endothelium-derived factors • gap junctions • microcirculation
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Circulation 2008 117: 987-989.
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