Cardiovascular Research Advance Access originally published online on May 19, 2009
Cardiovascular Research 2009 83(1):16-23; doi:10.1093/cvr/cvp156
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Inhibition of endothelial progenitor cell glycogen synthase kinase-3β results in attenuated neointima formation and enhanced re-endothelialization after arterial injury
1 University of Ottawa Heart Institute, Ottawa, Ontario, Canada
2 Faculty of Medicine, Department of Biochemistry Microbiology and Immunology, University of Ottawa Room H-263, 40 Ruskin Avenue, Ottawa, Ontario, Canada K1Y 4W7
* Corresponding author. Tel: +1 613 761 5030; Fax: +1 613 761 4237. E-mail address: 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 (GSK)-3β is a protein kinase that has been implicated in the 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 and results: 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 h and neointima formation at 7 and 14 days following injury. 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 
-4 integrin subunit, and improved adhesion, an effect which could be abrogated with an -4 integrin blocking antibody. EPCs without or with ex vivo GSKi treatment enhanced re-endothelialization 72 h 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.
Conclusion: 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