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

Circulation. 2005 Jun 28;111(25):3391-9. doi: 10.1161/CIRCULATIONAHA.104.527135. Epub 2005 Jun 13.


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Arterial Occlusive Diseases / therapy*
  • Cell Movement
  • Coculture Techniques
  • Endothelium, Vascular / cytology
  • Exercise Test
  • Exercise Therapy*
  • Growth Substances / blood
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Ischemia*
  • Ischemic Preconditioning
  • Middle Aged
  • Neovascularization, Physiologic
  • Peripheral Vascular Diseases / therapy*
  • RNA, Messenger / analysis
  • Receptors, CXCR4 / analysis
  • Receptors, CXCR4 / genetics
  • Vascular Endothelial Growth Factor A / blood


  • Growth Substances
  • RNA, Messenger
  • Receptors, CXCR4
  • Vascular Endothelial Growth Factor A