title: Role of caveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated by caveolin in endothelial cells.
abstract: 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.
  
  
  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.
authors.affiliation: Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Medical School, Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Saliez
authors.forename: C
authors.initials: C
authors.lastname: Bouzin
authors.forename: G
authors.initials: G
authors.lastname: Rath
authors.forename: P
authors.initials: P
authors.lastname: Ghisdal
authors.forename: F
authors.initials: F
authors.lastname: Desjardins
authors.forename: R
authors.initials: R
authors.lastname: Rezzani
authors.forename: L F
authors.initials: LF
authors.lastname: Rodella
authors.forename: J
authors.initials: J
authors.lastname: Vriens
authors.forename: B
authors.initials: B
authors.lastname: Nilius
authors.forename: O
authors.initials: O
authors.lastname: Feron
authors.forename: J-L
authors.initials: JL
authors.lastname: Balligand
authors.forename: C
authors.initials: C
authors.lastname: Dessy
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation / Q000502:physiology*; D017630:Connexins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D017629:Gap Junctions / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D009569:Nitric Oxide / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
chemical_list: D001685:Biological Factors; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D017630:Connexins; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D002118:Calcium