Published Online
on June 13, 2005

A more recent version of this article appeared on June 28, 2005

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Submitted on December 3, 2004
Revised on February 28, 2005
Accepted on March 8, 2005

Effects of Exercise and Ischemia on Mobilization and Functional Activation of Blood-Derived Progenitor Cells in Patients With Ischemic Syndromes. Results of 3 Randomized Studies

Marcus Sandri BSc, Volker Adams PhD, Stephan Gielen MD, Axel Linke MD, Karsten Lenk MD, Nicolle Kränkel PhD, Dominik Lenz PhD, Sandra Erbs MD, Dierk Scheinert MD, Friedrich Wilhelm Mohr MD, Gerhard Schuler MD, and Rainer Hambrecht MD^*

From the Heart Center (M.S., V.A., S.G., A.L., K.L., N.K., S.E., D.S., G.S., R.H.), Department of Internal Medicine/Cardiology; the Department of Pediatric Cardiology (D.L.); and the Department of Cardiac Surgery (F.W.M.), University of Leipzig, Leipzig, Germany.

^* To whom correspondence should be addressed. E-mail: hamr{at}medizin.uni-leipzig.de.

Background--Exercise training (ET) has been shown to improve regional perfusion in ischemic syndromes. This might be partially related to a regeneration of diseased endothelium by circulating progenitor cells (CPCs) or CPC-derived vasculogenesis. The aim of the present study was to determine whether ischemic stimuli during ET are required to promote CPC mobilization in patients with cardiovascular diseases.

Methods and Results--Patients with peripheral arterial occlusive disease (PAOD) were randomized to 4 weeks of daily ischemic ET or control (group A). Successfully revascularized patients with PAOD were randomized to 4 weeks of daily nonischemic ET or control (group B). Patients with stable coronary artery disease were subjected to 4 weeks of subischemic ET or control (group C). At baseline and after 4 weeks, the number of KDR⁺/CD34⁺ CPCs was determined by fluorescence-activated cell sorting analysis. Levels of vascular endothelial growth factor (VEGF) were measured by ELISA. A Matrigel assay was used to quantify CPC integration into vascular structures. Expression of the homing factor CXCR4 was determined by reverse transcription-polymerase chain reaction. In group A only, ischemic ET increased VEGF levels by 310% (P<0.05 versus control) associated with an increase in CPCs by 440% (P<0.05 versus control), increased CXCR4 expression, and enhanced integration of CPCs into endothelial networks. In contrast, subischemic ET in groups B and C increased CXCR4 expression and CPC integration.

Conclusions--In training programs, symptomatic tissue ischemia seems to be a prerequisite for CPC mobilization. However, ischemic and subischemic ET programs affect CXCR4 expression of CPCs, which might lead to an improved CPC integration into endothelial networks.

Key words: angiogenesis • exercise • stem cells

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