title: Thrombin-induced increase in endothelial permeability is associated with changes in cell-to-cell junction organization.
abstract: Thrombin increases endothelial permeability in a rapid and reversible way. This effect requires the catalytic activity of the enzyme and thrombin receptor engagement. Endothelial cell permeability is mostly regulated by intercellular junction organization. In the present study, we investigated whether opening of intercellular gaps after thrombin treatment could be related to changes in adherence-junction molecular organization. By immunofluorescence analysis, we found that thrombin stimulation of endothelial cells caused a marked alteration of the distribution of vascular endothelial (VE)-cadherin and of the associated catenins. These molecules, which are strictly localized at intercellular boundaries in confluent resting cells, were absent in the areas of intercellular retraction. Immunoprecipitation analysis indicated that thrombin disrupted the VE-cadherin/catenin complex. This effect was reversible and correlated with the increase in endothelial permeability. The use of a protein kinase C inhibitor (calphostin C) blocked both thrombin-induced permeability and disassembly of adherence-junction components. We propose that thrombin's effect on endothelial cell junction organization is an important determinant in the increase in endothelial permeability induced by this agent.
authors.affiliation: CEA, Laboratoire d'Hématologie, INSERM U217, Département de Biologie Moléculaire et Structurale, Grenoble, France.
authors.forename: M J
authors.initials: MJ
authors.lastname: Rabiet
authors.forename: J L
authors.initials: JL
authors.lastname: Plantier
authors.forename: Y
authors.initials: Y
authors.lastname: Rival
authors.forename: Y
authors.initials: Y
authors.lastname: Genoux
authors.forename: M G
authors.initials: MG
authors.lastname: Lampugnani
authors.forename: E
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000595:Amino Acid Sequence; D015820:Cadherins / Q000032:analysis; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects*; D008969:Molecular Sequence Data; D010539:Permeability; D010766:Phosphorylation; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D015820:Cadherins; D013917:Thrombin