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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



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ID: 717318.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin
Authors:Frye, M.; Dierkes, M.; Kuppers, V.; Vockel, M.; Tomm, J.; Zeuschner, D.; Rossaint, J.; Zarbock, A.; Koh, G. Y.; Peters, K.; Nottebaum, A. F.; Vestweber, D.
Date of Publication (YYYY-MM-DD):2015-12-14
Title of Journal:J Exp Med
Volume:212
Issue / Number:13
Start Page:2267
End Page:2287
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Electron Microscopy Unit, Max Planck Institute for Molecular Biomedicine, D-48149 Munster, Germany. Department of Anesthesiology and Critical Care Medicine, University of Munster, D-48149 Munster, Germany. 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. Aerpio Therapeutics, Cincinnati, OH 45242. Max Planck Institute for Molecular Biomedicine, D-48149 Munster, Germany vestweb@mpi-muenster.mpg.de.
Identifiers:ISSN:1540-9538 (Electronic) 0022-1007 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/26642851 [ID No:2]
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