Effects of Exercise and Ischemia on Mobilization and Functional Activation of Blood-Derived Progenitor Cells in Patients With Ischemic Syndromes

Abstract

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 ϩ /CD34 ϩ 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% (PϽ0.05 versus control) associated with an increase in CPCs by 440% (PϽ0.05 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. (Circulation. 2005;111:3391-3399.)

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

“…In humans, Sandri and coworkers 103 were able to show that exercise training for 4 weeks improves the expression of homing factor CXCR4 on the surface of CPCs, which mediates the incorporation of CPCs into vascular structures. Furthermore, exercise training enhances functional CPC capacity in patients with CAD, which is essential for the formation of new vascular structures through vasculogenesis 103. However, the authors failed to determine any effect of the exercise training intervention on the gross number of CPCs in this study cohort.…”

Endothelial progenitor cells: Implications for cardiovascular disease

“…Moreover, the function of CPCs analyzed by Matrigel assay was significantly enhanced after 4 weeks. These aforementioned changes in number and function of CPCs were associated with an improvement in symptom-free and maximal walking distances (9).…”

“…What are proper negative controls to set the gate for cell quantification? Several different negative controls are currently used in the different studies, ranging from isotype specific antibodies labeled with the same colors as the specific antibodies (8)(9)(10), addition of no antibodies at all to see the autofluorescence of the cells, to the fluorescence minus one (FMO) strategy [reviewed in (11)]. Another factor complicating the characterization of EPCs is the fact that the expression of the often used stem cell marker CD34 is not only restricted to stem cells, but is also expressed on mature microvascular endothelial cells (12,13).…”

“…After the isolation, the cells are plated on cell culture dishes coated with either fibronectin (19)(20)(21) or gelatin (8,9,22). Already these variations in the coating strategy may have an influence on the results obtained by cell culture with respect to cell number, cell phenotype, and cell function.…”

“…Stem cells within the bone marrow usually exist in a quiescent state and specific signals stimulate the stem cells to differentiate and to be mobilized into the systemic circulation. Beside humoral factors such as cytokines (51)(52)(53), hormones (51,53,54), chemokines (37,55), and drugs (56-58), exercise training (ET) has been shown to increase the number of circulating EPCs (8,9,59,60).…”