Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis

Background - The molecular mechanisms by which physical training improves peripheral and coronary artery disease are poorly understood. Bone marrow - derived endothelial progenitor cells (EPCs) are thought to exert beneficial effects on atherosclerosis, angiogenesis, and vascular repair. Methods and Results - To study the effect of physical activity on the bone marrow, EPCs were quantified by fluorescence-activated cell sorter analysis in mice randomized to running wheels (5.1 +/- 0.8 km/d, n = 12 to 16 per group) or no running wheel. Numbers of EPCs circulating in the peripheral blood of trained mice were enhanced to 267 +/- 19%, 289 +/- 22%, and 280 +/- 25% of control levels after 7, 14, and 28 days, respectively, accompanied by a similar increase of EPCs in the bone marrow and EPCs expanded from spleen-derived mononuclear cells. eNOS(-/-) mice and wild-type mice treated with N-G-nitro-L-arginine methyl ester showed lower EPC numbers at baseline and a significantly attenuated increase of EPC in response to physical activity. Exercise NO dependently increased serum levels of vascular endothelial growth factor and reduced the rate of apoptosis in spleen-derived EPCs. Running inhibited neointima formation after carotid artery injury by 22 +/- 2%. Neoangiogenesis, as assessed in a subcutaneous disc model, was increased by 41 +/- 16% compared with controls. In patients with stable coronary artery disease ( n = 19), moderate exercise training for 28 days led to a significant increase in circulating EPCs and reduced EPC apoptosis. Conclusions - Physical activity increases the production and circulating numbers of EPCs via a partially NO-dependent, antiapoptotic effect that could potentially underlie exercise-related beneficial effects on cardiovascular diseases.