title: Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking.
abstract: BACKGROUND
  Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is expressed and secreted by endothelial cells. Patients with PAI-1 deficiency show a mild to moderate bleeding diathesis, which has been exclusively ascribed to the function of PAI-1 in down-regulating fibrinolysis. We tested the hypothesis that PAI-1 function plays a direct role in controlling vascular integrity and permeability by keeping endothelial cell-cell junctions intact.
  
  
  RESULTS
  We utilized PAI-039, a specific small molecule inhibitor of PAI-1, to investigate the role of PAI-1 in protecting endothelial integrity. In vivo inhibition of PAI-1 resulted in vascular leakage from intersegmental vessels and in the hindbrain of zebrafish embryos. In addition PAI-1 inhibition in human umbilical vein endothelial cell (HUVEC) monolayers leads to a marked decrease of transendothelial resistance and disrupted endothelial junctions. The total level of the endothelial junction regulator VE-cadherin was reduced, whereas surface VE-cadherin expression was unaltered. Moreover, PAI-1 inhibition reduced the shedding of VE-cadherin. Finally, we detected an accumulation of VE-cadherin at the Golgi apparatus.
  
  
  CONCLUSIONS
  Our findings indicate that PAI-1 function is important for the maintenance of endothelial monolayer and vascular integrity by controlling VE-cadherin trafficking to and from the plasma membrane. Our data further suggest that therapies using PAI-1 antagonists like PAI-039 ought to be used with caution to avoid disruption of the vessel wall.
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Daniel
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Timmerman
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Igor
authors.initials: I
authors.lastname: Kovacevic
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Luc
authors.initials: L
authors.lastname: Adriaanse
authors.affiliation: Department of Cell Biology, Biozentrum der Universität Basel, Basel, Switzerland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Paatero
authors.affiliation: Department of Cell Biology, Biozentrum der Universität Basel, Basel, Switzerland.
authors.forename: Heinz-Georg
authors.initials: HG
authors.lastname: Belting
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology; D007365:Intercellular Junctions / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D015027:Zebrafish
chemical_list: D015820:Cadherins; D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin