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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 19, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp156
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Inhibition of Endothelial Progenitor Cell GSK 3β Results in Attenuated Neointima Formation and Enhanced Re-endothelialization after Arterial Injury

Benjamin Hibbert, MD1, Xiaoli Ma, MD PhD1, Ali Pourdjabbar, MSc1, Erik Holm, BSc1, Katey Rayner, PhD1, Yong-Xiang Chen, MD PhD1, Jiangfeng Sun, MD PhD1, Lionel Filion, PhD2 and Edward R. O'Brien, MD1,*

1 University of Ottawa Heart Institute, Ottawa, Ontario, Canada
2 Department of Biochemistry Microbiology and Immunology, Faculty of Medicine, University of Ottawa

* Room H-263, 40 Ruskin Avenue, Ottawa, Ontario, Canada K1Y 4W7, Tel. 613-761-5030, Fax. 613-761-4237, Email: eobrien{at}ottawaheart.ca

Aims: Endothelial progenitor cells (EPCs) are circulating pluripotent vascular cells capable of enhancing re-endothelialization and diminishing neointima formation following arterial injury. Glycogen synthase kinase 3β (GSK) is a protein kinase that has been implicated in regulation of progenitor cell biology. We hypothesized that EPC abundance and function could be enhanced with the use of an inhibitor of GSK 3β (GSKi), thereby resulting in improved arterial repair.

Methods: Human EPCs were expanded ex vivo, treated with a specific GSKi, and then assessed for both yield and functional characteristics by in vitro assays for adherence, apoptosis, and survival. In vivo functionality of treated human EPCs was assessed in immune-tolerant mice subjected to femoral artery wire injury. Re-endothelialization was assessed at 72 hours and neointima formation at 7 and 14 days following injury.

Results: GSKi treatment resulted in an improvement in the yield of EPCs and a reduction in apoptosis in cells derived from both healthy controls and patients with coronary artery disease. Treatment also increased vascular endothelial growth factor secretion, up-regulated expression of mRNA for the {alpha}-4 integrin subunit, and improved adhesion, an effect which could be abrogated with an {alpha}-4 integrin blocking antibody. EPCs without or with ex vivo GSKi treatment enhanced re-endothelialization 72 hours following injury as well as reduced neointima formation at 7 days (e.g., endothelial coverage: 7.2±1.7% vs. 70.7±5.8% vs. 87.2±4.1%; intima to media ratios: 1.05±0.19 vs. 0.39±0.08 vs. 0.14 ±0.02; p<0.05 for all comparisons), an effect that was persistent at 14 days.

Conclusions: GSKi improves the functional profile of EPCs and is associated with improved re-endothelialization and reduced neointima formation following injury.

KEYWORDS endothelial progenitor cells; glycogen synthase kinase; neointima; re-endothelialization; vascular endothelial growth factor; integrin

Time for primary review: 13 Days


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