title: Caveolin-1 opens endothelial cell junctions by targeting catenins.
abstract: OBJECTIVE
  A fundamental phenomenon in inflammation is the loss of endothelial barrier function, in which the opening of endothelial cell junctions plays a central role. However, the molecular mechanisms that ultimately open the cell junctions are largely unknown.
  
  
  RESULTS
  Impedance spectroscopy, biochemistry, and morphology were used to investigate the role of caveolin-1 in the regulation of thrombin-induced opening of cell junctions in cultured human and mouse endothelial cells. Here, we demonstrate that the vascular endothelial (VE) cadherin/catenin complex targets caveolin-1 to endothelial cell junctions. Association of caveolin-1 with VE-cadherin/catenin complexes is essential for the barrier function decrease in response to the pro-inflammatory mediator thrombin, which causes a reorganization of the complex in a rope ladder-like pattern accompanied by a loss of junction-associated actin filaments. Mechanistically, we show that in response to thrombin stimulation the protease-activated receptor 1 (PAR-1) causes phosphorylation of caveolin-1, which increasingly associates with β- and γ-catenin. Consequently, the association of β- and γ-catenin with VE-cadherin is weakened, thus allowing junction reorganization and a decrease in barrier function. Thrombin-induced opening of cell junctions is lost in caveolin-1-knockout endothelial cells and after expression of a Y/F-caveolin-1 mutant but is completely reconstituted after expression of wild-type caveolin-1.
  
  
  CONCLUSIONS
  Our results highlight the pivotal role of caveolin-1 in VE-cadherin-mediated cell adhesion via catenins and, in turn, in barrier function regulation.
authors.affiliation: Institute of Physiology, Medical Faculty of the TU-Dresden, Germany.
authors.forename: Romy
authors.initials: R
authors.lastname: Kronstein
authors.forename: Jochen
authors.initials: J
authors.lastname: Seebach
authors.forename: Sylvia
authors.initials: S
authors.lastname: Grossklaus
authors.forename: Carsten
authors.initials: C
authors.lastname: Minten
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Marek
authors.initials: M
authors.lastname: Drab
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebner
authors.forename: Yvan
authors.initials: Y
authors.lastname: Arsenijevic
authors.forename: Abdallah Abu
authors.initials: AA
authors.lastname: Taha
authors.forename: Tatiana
authors.initials: T
authors.lastname: Afanasieva
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schnittler
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D016466:CHO Cells; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000378:metabolism*; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D051242:Caveolin 1; D017931:DNA Primers; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D013917:Thrombin; D000099152:Cadherin 5