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First published online May 6, 2009
doi: 10.1242/10.1242/jcs.040212

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Endothelial barrier stabilization by a cyclic tandem peptide targeting VE-cadherin transinteraction in vitro and in vivo

Wolfgang-Moritz Heupel^1,*, Athina Efthymiadis^1,*, Nicolas Schlegel¹, Thomas Müller², Yvonne Baumer¹, Werner Baumgartner³, Detlev Drenckhahn^1, and Jens Waschke^1,

¹ University of Würzburg, Institute of Anatomy and Cell Biology, Koellikerstr. 6, D-97070 Würzburg, Germany
² University of Würzburg, Department of Botany I, Julius-von-Sachs-Platz 2, D-97082 Würzburg, Germany
³ RWTH Aachen, Institute of Biology II, Kopernikusstr. 16, D-52056 Aachen, Germany

Authors for correspondence: (e-mails: jens.waschke{at}mail.uni-wuerzburg.de; drenckhahn{at}uni-wuerzburg.de)

Accepted 28 January 2009

Inflammatory stimuli result in vascular leakage with potentially life threatening consequences. As a key barrier component, loss of vascular endothelial (VE-) cadherin-mediated adhesion often precedes endothelial breakdown. This study aimed to stabilize VE-cadherin transinteraction and endothelial barrier function using peptides targeting the VE-cadherin adhesive interface. After modelling the transinteracting VE-cadherin structure, an inhibiting single peptide (SP) against a VE-cadherin binding pocket was selected, which specifically blocked VE-cadherin transinteraction as analyzed by single molecule atomic force microscopy (AFM). The tandem peptide (TP) consisting of two SP sequences in tandem was designed to strengthen VE-cadherin adhesion by simultaneously binding and cross-bridging two interacting cadherin molecules. Indeed, in AFM experiments TP specifically rendered VE-cadherin transinteraction resistant against an inhibitory monoclonal antibody. Moreover, TP reduced VE-cadherin lateral mobility and enhanced binding of VE-cadherin-coated microbeads to cultured endothelial cells, but acted independently of the actin cytoskeleton. TP also stabilized endothelial barrier properties against the Ca²⁺ ionophore A23187 and the inhibitory antibody. Finally, TP abolished endothelial permeability increase induced by tumour necrosis factor- in microperfused venules in vivo. Stabilization of VE-cadherin adhesion by cross-bridging peptides may therefore be a novel therapeutic approach for the treatment of vascular hyperpermeability.

Key words: VE-cadherin, Endothelial barrier, TNF-, Peptide, Inflammation

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