Artificially stabilizing contacts between VE-cadherin and VE-PTP reduce vascular permeability and leukocyte extravasation in vivo

Alexander Zarbock

Allingham

Andre Broermann

Astrid Fee Nottebaum

Bixel

Breviario

Bäumer

Carman

Corada

Crosby

Dietmar Vestweber

Dörte Schulte

Ebnet

Fachinger

Giuseppe Cagna

Gotsch

Helena Block

Jan Rossaint

Koblizek

Maike Frye

Mamdouh

Mamluk

Mark Winderlich

Martìn-Padura

Matsuyoshi

Mempel

Muller

Nawroth

Nottebaum

Nourshargh

Ruth Linnepe

Schenkel

Schulte

Turowski

Vestweber

Wegmann

Zarbock

English

PubMed

We have recently shown that vascular endothelial protein tyrosine phosphatase (VE-PTP), an endothelial membrane protein, associates with VE-cadherin and is required for optimal VE-cadherin function and endothelial cell contact integrity. The dissociation of VE-PTP from VE-cadherin is triggered by vascular endothelial growth factor (VEGF) and by the binding of leukocytes to endothelial cells in vitro, suggesting that this dissociation is a prerequisite for the destabilization of endothelial cell contacts. Here, we show that VE-cadherin/VE-PTP dissociation also occurs in vivo in response to LPS stimulation of the lung or systemic VEGF stimulation. To show that this dissociation is indeed necessary in vivo for leukocyte extravasation and VEGF-induced vascular permeability, we generated knock-in mice expressing the fusion proteins VE-cadherin-FK 506 binding protein and VE-PTP-FRB* under the control of the endogenous VE-cadherin promoter, thus replacing endogenous VE-cadherin. The additional domains in both fusion proteins allow the heterodimeric complex to be stabilized by a chemical compound (rapalog). We found that intravenous application of the rapalog strongly inhibited VEGF-induced (skin) and LPS-induced (lung) vascular permeability and inhibited neutrophil extravasation in the IL-1β inflamed cremaster and the LPS-inflamed lung. We conclude that the dissociation of VE-PTP from VE-cadherin is indeed required in vivo for the opening of endothelial cell contacts during induction of vascular permeability and leukocyte extravasation.</jats:p

Crossref

The Journal of Experimental Medicine

Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3256962

Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo

Abstract

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