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J Exp Med. 2015 Dec 14;212(13):2267-87. doi: 10.1084/jem.20150718. Epub 2015 Dec 7.

Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin.

Author information

1
Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
2
Electron Microscopy Unit, Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany.
3
Department of Anesthesiology and Critical Care Medicine, University of Münster, D-48149 Münster, Germany.
4
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.
5
Aerpio Therapeutics, Cincinnati, OH 45242.
6
Max Planck Institute for Molecular Biomedicine, D-48149 Münster, Germany vestweb@mpi-muenster.mpg.de.

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.

PMID:
26642851
PMCID:
PMC4689167
DOI:
10.1084/jem.20150718
[Indexed for MEDLINE]
Free PMC Article

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