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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 19, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn127
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Nuclear targeting of β-catenin and p120ctn during thrombin induced endothelial barrier dysfunction

Cora M.L. Beckers1, Juan J. García-Vallejo2, Victor W.M. van Hinsbergh1 and Geerten P. van Nieuw Amerongen1,*

1 VU University Medical Center, Institute for Cardiovascular Research, department for Physiology, van der Boechorststraat 7, 1108 BH Amsterdam, the Netherlands
2 Department of Molecular Cell Biology & Immunology, van der Boechorststraat 7, 1108 BH Amsterdam, the Netherlands

* Corresponding author. VU University Medical Center, Institute for Cardiovascular Research, department for Physiology, van der Boechorststraat 7, 1108 BH Amsterdam, the Netherlands. Tel.: +31 20 4441748; fax: +31 20 4448255. E-mail address: nieuwamerongen{at}vumc.nl

Aim: Cytosolic and nuclear localization of β-catenin was observed in leaky vessels and in tumors. Several lines of evidence indicate that nuclear β-catenin facilitates angiogenesis. We hypothesized, that nuclear β-catenin liberated from endothelial junctional complexes marks the transition from hyperpermeability to angiogenesis. The aim of this study was therefore, to investigate the fate of β-catenin and the related catenin p120ctn, during disruption of the endothelial barrier function in human umbilical vein endothelial cells.

Methods & Results: The hyperpermeability-inducer thrombin caused a Rho kinase dependent redistribution of β-catenin from the membrane to the cytosol as evidenced by western blot analysis of membrane and cytosol fractions and by immunohistochemistry. Glycogen synthase kinase 3β, which phosphorylates cytosolic β-catenin and thereby facilitates its proteasomal degradation, was inhibited by thrombin. Analysis of nuclear extracts demonstrated a thrombin-induced nuclear accumulation of β-catenin as well as p120ctn. Thrombin stimulation activated β-catenin-mediated transcriptional activity as evidenced by reporter assays. Finally, real time-PCR revealed increased mRNA levels of several β-catenin target genes.

Conclusions: Thrombin induced a cytosolic stabilization of membrane-liberated β-catenin, which, together with p120ctn, subsequently translocated to the nucleus where it induces several β-catenin target genes. This supports the suggestion that membrane-liberated β-catenin and p120ctn contribute to angiogenic responses of endothelial cells following episodes of vascular leakage.

KEYWORDS angiogenesis; capillary permeability; cell communication; signal transduction; vasoactive agents

Time for primary review: 33 days

Abbreviations: adenomatosis poliposis coli (APC), adherens junctions (AJs), endothelial cells (ECs), glycogen synthase kinase (GSK) 3β, human umbilical vein endothelial cells (HUVECs), p120catenin (p120ctn), T cell factor / leukocyte enhancing factor (Tcf/LEF), vascular endothelial (VE)-cadherin.


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