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Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia

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Abstract

Purpose

We aimed to evaluate whether ischemia is required for erythropoietin (EPO) induced stimulation of endothelial progenitor cells (EPCs) and their related effects on endothelial and cardiac function.

Methods

Bone marrow of rats was replaced by transgenic cells to allow tracking of EPCs. Ischemic heart failure was induced by left coronary artery ligation to induce myocardial infarction (MI) and control rats received a sham procedure. Three weeks after surgery, rats were randomized to receive EPO (darbepoetin alfa 40 μg/kg per 3 weeks) or vehicle and were sacrificed 9 weeks after surgery.

Results

In all treated groups, EPO significantly increased circulating EPCs and their incorporation into the endothelium of the ischemic and non-ischemic hearts as well as in the control organs; kidney and liver. This was associated with significantly improved endothelial function, which was strongly correlated with circulating EPCs (R = 0.7, p < 0.01). However, additional EPCs preferentially homed to the ischemic MI borderzone (p < 0.01) resulting in specific EPO-induced improvement of cardiac microvascularization and performance only in ischemic hearts (all p < 0.05). The differential stimulation of neovascularization by EPO was associated with increased EPO-receptor and VEGF expression in ischemic hearts only.

Conclusions

In general, EPO stimulates normal endothelial progenitor cell-mediated endothelial turnover, but improves cardiac microvascularization and function only in the presence of ischemia.

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Acknowledgements

We thank Bianca Meijeringh and Jan Roggeveld for expert technical assistance. Dr. Westenbrink and dr. van der Harst are supported by the Netherlands Organisation for Scientific Research and dr. Belonje is supported by the Netherlands heart foundation. H. Oeseburg is supported by GUIDE. Dr. van Veldhuisen and Dr. Voors are established investigators of the Netherlands Heart Foundation (grant D97-017 and grant 2006T037 respectively).

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Authors and Affiliations

  1. Department of Cardiology, Thoraxcenter, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB, Groningen, The Netherlands

    B. Daan Westenbrink, Hisko Oeseburg, Lennaert Kleijn, Pim van der Harst, Anne M. S. Belonje, Adriaan A. Voors, Regien G. Schoemaker, Rudolf A. de Boer, Dirk J. van Veldhuisen & Wiek H. van Gilst

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  1. B. Daan Westenbrink
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  3. Lennaert Kleijn
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Correspondence to B. Daan Westenbrink.

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Westenbrink, B.D., Oeseburg, H., Kleijn, L. et al. Erythropoietin Stimulates Normal Endothelial Progenitor Cell-Mediated Endothelial Turnover, but Attributes to Neovascularization Only in the Presence of Local Ischemia. Cardiovasc Drugs Ther 22, 265–274 (2008). https://doi.org/10.1007/s10557-008-6094-y

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  • DOI: https://doi.org/10.1007/s10557-008-6094-y

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