Published Online
on September 27, 2004

A more recent version of this article appeared on October 5, 2004

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Submitted on October 21, 2003
Revised on May 17, 2004
Accepted on May 20, 2004

Cytokine-Induced Mobilization of Circulating Endothelial Progenitor Cells Enhances Repair of Injured Arteries

Deling Kong PhD, Luis G. Melo PhD, Massimiliano Gnecchi MD, Lunan Zhang MD, Gustavo Mostoslavsky MD, PhD, Chong C. Liew PhD, Richard E. Pratt PhD, and Victor J. Dzau MD^*

From the Department of Medicine (D.K., L.G.M., M.G., L.Z., C.C.L., R.E.P., V.J.D.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; the Department of Physiology (L.G.M.), Queen’s University, Kingston, Ontario, Canada; and the Department of Genetics (G.M.), Children’s Hospital, Boston, Mass. Dr Kong is currently at the School of Life Science, Nankai University, Tianjin, China.

^* To whom correspondence should be addressed. E-mail: victor.dzau{at}duke.edu.

Background--The existence of circulating endothelial progenitor cells (CEPCs) has previously been documented. These cells can be mobilized by cytokines and are recruited to sites of injury, where they may participate in tissue repair. In the present study, we examined the hypothesis that mobilization of CEPCs by exogenous granulocyte-colony stimulating factor (G-CSF) enhances repair of injured arteries by facilitating reendothelialization and inhibiting neointima development.

Methods and Results--Male rats were injected daily with 50 µg/kg recombinant human G-CSF or 0.9% NaCl SC for 8 days. On the fifth day of treatment, 1 mL of blood was collected for fluorescence-activated cell sorting analysis of mononuclear cells, and the animals underwent balloon angioplasty of the common carotid artery. The animals were killed at 2 or 4 weeks after injury, and the carotid arteries were harvested and processed for immunohistochemistry, scanning electron microscopy (SEM), and morphometric analysis of endothelialization and neointimal formation. G-CSF increased the number of circulating mononuclear cells that express endothelial cell lineage markers several-fold. SEM and immunohistochemical staining with the endothelial marker, platelet and endothelial cell adhesion molecule-1, showed rapid and nearly complete (>90%) reendothelialization of the denuded vessels in the G-CSF-treated animals compared with <20% in the control animals. Reendothelialization was paralleled by a decrease in inflammation in the vessel wall. Neointima thickness was reduced by 60% in the G-CSF-treated animals compared with control animals at 2 and 4 weeks after injury.

Conclusion--We postulate that cytokine-induced mobilization of CEPCs may be a suitable therapeutic strategy for prevention of restenosis after revascularization procedures.

Key words: growth substances • restenosis • endothelium • immunohistochemistry

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