Caveolin-1 opens endothelial cell junctions by targeting catenins

Cardiovasc Res. 2012 Jan 1;93(1):130-40. doi: 10.1093/cvr/cvr256. Epub 2011 Sep 29.

Abstract

Aims: 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.

Methods and 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.

Conclusion: Our results highlight the pivotal role of caveolin-1 in VE-cadherin-mediated cell adhesion via catenins and, in turn, in barrier function regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Base Sequence
  • CHO Cells
  • Cadherins / metabolism
  • Catenins / metabolism*
  • Caveolin 1 / deficiency
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Cell Line
  • Cricetinae
  • Cricetulus
  • DNA Primers / genetics
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intercellular Junctions / drug effects
  • Intercellular Junctions / metabolism*
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Thrombin / pharmacology

Substances

  • Antigens, CD
  • Cadherins
  • Catenins
  • Caveolin 1
  • DNA Primers
  • Multiprotein Complexes
  • Mutant Proteins
  • cadherin 5
  • Thrombin