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

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.