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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 30, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn108
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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

Ethanol Stimulates Endothelial Cell Angiogenic Activity via a Notch- and Angiopoietin 1-dependent pathway

David Morrow, PhD1, John P. Cullen, PhD1, Paul A. Cahill, PhD2 and Eileen M. Redmond, PhD1

1 Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642
2 Vascular Health Research Centre, Dublin City University, Dublin, Ireland

Corresponding author: Dr. Eileen M. Redmond, University of Rochester Medical Center, Department of Surgery, Box SURG, 601 Elmwood Avenue, Rochester, NY, 14642-8410 Tel: (585) 275-2870 Fax: (585)756-7819 E-mail: Eileen_Redmond{at}urmc.rochester.edu

Aims: Our aims were to determine the effect of alcohol (EtOH) on endothelial angiogenic activity and to delineate the cell signaling mechanisms involved.

Methods and Results: Treatment of human umbilical vein endothelial cells (HUVEC) with EtOH (1-100 mM, 24 h) dose-dependently increased their network formation on matrigel (an index of angiogenesis) with a maximum response (2.5 - 3 fold increase) at 25 mM. Ethanol also stimulated the proliferation (by cell count and proliferating cell nuclear antigen (PCNA) expression) and migration (by scratch wound assay) of HUVEC. In parallel cultures, EtOH stimulated Notch receptor (1 and 4) and Notch target gene (hrt-1, 2, 3) mRNA and protein expression and enhanced CBF-1/RBP-Jk promoter activity. EtOH also stimulated, at the mRNA and protein level, the expression of angiopoietin 1 (Ang1) and its Tie2 receptor in these cells. Knockdown of Notch 1 or 4 by siRNA or inhibition of Notch-mediated, CBF-1/RBP-Jk-regulated gene expression by the Epstein-Barr virus-encoded protein RPMS-1 inhibited both ethanol-induced Ang1/Tie2 expression in HUVEC and their network formation on matrigel. Moreover, knockdown of Ang1 or Tie2 by siRNA inhibited ethanol-induced endothelial network formation.

Conclusions: These data demonstrate that ethanol, at levels consistent with moderate consumption, enhances endothelial angiogenic activity in vitro by stimulating a novel Notch/CBF-1/RBP-JK - Ang1/Tie2- dependent pathway. These actions of ethanol may be relevant to the cardiovascular effects of alcohol consumption purported by epidemiological studies.

Time for primary review: 68 days


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