title: Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin.
abstract: Vascular endothelial (VE)-protein tyrosine phosphatase (PTP) associates with VE-cadherin, thereby supporting its adhesive activity and endothelial junction integrity. VE-PTP also associates with Tie-2, dampening the tyrosine kinase activity of this receptor that can support stabilization of endothelial junctions. Here, we have analyzed how interference with VE-PTP affects the stability of endothelial junctions in vivo. Blocking VE-PTP by antibodies, a specific pharmacological inhibitor (AKB-9778), and gene ablation counteracted vascular leak induction by inflammatory mediators. In addition, leukocyte transmigration through the endothelial barrier was attenuated. Interference with Tie-2 expression in vivo reversed junction-stabilizing effects of AKB-9778 into junction-destabilizing effects. Furthermore, lack of Tie-2 was sufficient to weaken the vessel barrier. Mechanistically, inhibition of VE-PTP stabilized endothelial junctions via Tie-2, which triggered activation of Rap1, which then caused the dissolution of radial stress fibers via Rac1 and suppression of nonmuscle myosin II. Remarkably, VE-cadherin gene ablation did not abolish the junction-stabilizing effect of the VE-PTP inhibitor. Collectively, we conclude that inhibition of VE-PTP stabilizes challenged endothelial junctions in vivo via Tie-2 by a VE-cadherin-independent mechanism. In the absence of Tie-2, however, VE-PTP inhibition destabilizes endothelial barrier integrity in agreement with the VE-cadherin-supportive effect of VE-PTP.
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Frye
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Dierkes
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Küppers
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Vockel
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Tomm
authors.affiliation: Electron Microscopy Unit, Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Zeuschner
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Münster, D-48149 Münster, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Münster, D-48149 Münster, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.affiliation: Center for Vascular Research, Institute of Basic Science, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: Aerpio Therapeutics, Cincinnati, OH 45242.
authors.forename: Kevin
authors.initials: K
authors.lastname: Peters
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Astrid Fee
authors.initials: AF
authors.lastname: Nottebaum
authors.affiliation: Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany vestweb@mpi-muenster.mpg.de.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000172:deficiency* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D017353:Gene Deletion; D020868:Gene Silencing / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013451:Sulfonic Acids / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000814:Aniline Compounds; D015703:Antigens, CD; D015820:Cadherins; D019000:Phosphotyrosine; D034741:RNA, Small Interfering; D042787:Receptor, TIE-2; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D011993:Recombinant Fusion Proteins; D013451:Sulfonic Acids; D020827:rap1 GTP-Binding Proteins; D000099152:Cadherin 5; C000598564:AKB-9778; C515576:COMP-Ang1 fusion protein