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

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Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. / Frye, Maike; Dierkes, Martina; Küppers, Verena; Vockel, Matthias; Tomm, Janina; Zeuschner, Dagmar; Rossaint, Jan; Zarbock, Alexander; Koh, Gou Young; Peters, Kevin; Nottebaum, Astrid Fee; Vestweber, Dietmar.

In: J EXP MED, Vol. 212, No. 13, 14.12.2015, p. 2267-87.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Frye, M, Dierkes, M, Küppers, V, Vockel, M, Tomm, J, Zeuschner, D, Rossaint, J, Zarbock, A, Koh, GY, Peters, K, Nottebaum, AF & Vestweber, D 2015, 'Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin', J EXP MED, vol. 212, no. 13, pp. 2267-87. https://doi.org/10.1084/jem.20150718

APA

Frye, M., Dierkes, M., Küppers, V., Vockel, M., Tomm, J., Zeuschner, D., Rossaint, J., Zarbock, A., Koh, G. Y., Peters, K., Nottebaum, A. F., & Vestweber, D. (2015). Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. J EXP MED, 212(13), 2267-87. https://doi.org/10.1084/jem.20150718

Vancouver

Frye M, Dierkes M, Küppers V, Vockel M, Tomm J, Zeuschner D et al. Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. J EXP MED. 2015 Dec 14;212(13):2267-87. https://doi.org/10.1084/jem.20150718

Bibtex

@article{08b6f14feed34c809f19ea7abfc01f8b,
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.",
keywords = "Aniline Compounds, Animals, Antigens, CD, Cadherins, Capillary Permeability, Cell Movement, Endothelial Cells, Gene Deletion, Gene Silencing, Human Umbilical Vein Endothelial Cells, Mice, Inbred C57BL, Mice, Knockout, Neutrophils, Phosphorylation, Phosphotyrosine, RNA, Small Interfering, Receptor, TIE-2, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Recombinant Fusion Proteins, Sulfonic Acids, rap1 GTP-Binding Proteins, Journal Article, Research Support, Non-U.S. Gov't",
author = "Maike Frye and Martina Dierkes and Verena K{\"u}ppers and Matthias Vockel and Janina Tomm and Dagmar Zeuschner and Jan Rossaint and Alexander Zarbock and Koh, {Gou Young} and Kevin Peters and Nottebaum, {Astrid Fee} and Dietmar Vestweber",
note = "{\textcopyright} 2015 Frye et al.",
year = "2015",
month = dec,
day = "14",
doi = "10.1084/jem.20150718",
language = "English",
volume = "212",
pages = "2267--87",
journal = "J EXP MED",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "13",

}

RIS

TY - JOUR

T1 - Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin

AU - Frye, Maike

AU - Dierkes, Martina

AU - Küppers, Verena

AU - Vockel, Matthias

AU - Tomm, Janina

AU - Zeuschner, Dagmar

AU - Rossaint, Jan

AU - Zarbock, Alexander

AU - Koh, Gou Young

AU - Peters, Kevin

AU - Nottebaum, Astrid Fee

AU - Vestweber, Dietmar

N1 - © 2015 Frye et al.

PY - 2015/12/14

Y1 - 2015/12/14

N2 - 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.

AB - 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.

KW - Aniline Compounds

KW - Animals

KW - Antigens, CD

KW - Cadherins

KW - Capillary Permeability

KW - Cell Movement

KW - Endothelial Cells

KW - Gene Deletion

KW - Gene Silencing

KW - Human Umbilical Vein Endothelial Cells

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neutrophils

KW - Phosphorylation

KW - Phosphotyrosine

KW - RNA, Small Interfering

KW - Receptor, TIE-2

KW - Receptor-Like Protein Tyrosine Phosphatases, Class 3

KW - Recombinant Fusion Proteins

KW - Sulfonic Acids

KW - rap1 GTP-Binding Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1084/jem.20150718

DO - 10.1084/jem.20150718

M3 - SCORING: Journal article

C2 - 26642851

VL - 212

SP - 2267

EP - 2287

JO - J EXP MED

JF - J EXP MED

SN - 0022-1007

IS - 13

ER -