Physical Training Increases Endothelial Progenitor Cells, Inhibits Neointima Formation, and Enhances Angiogenesis

Abstract

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 (5.1Ϯ0.8 km/d, nϭ12 to 16 per group) or no running wheel. Numbers of EPCs circulating in the peripheral blood of trained mice were enhanced to 267Ϯ19%, 289Ϯ22%, and 280Ϯ25% 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 Ϫ/Ϫ 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 22Ϯ2%. Neoangiogenesis, as assessed in a subcutaneous disc model, was increased by 41Ϯ16% compared with controls. In patients with stable coronary artery disease (nϭ19), 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.

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

“…In addition, the beneficial effects of exercise training on remodeling, reendothelialization, and neointimal hyperplasia in response to endothelial injury have been shown to be mainly dependent on NO availability in a rat model of long‐term eNOS inhibition. As previously mentioned, the liberation of CPCs from bone marrow in response to exercise was shown to be inhibited in eNOS knockout mice and by N‐methylarginine infusion in humans 53, 55, 86. The CPC number correlated with endothelial function in these subjects.…”

“…However, the authors failed to determine any effect of the exercise training intervention on the gross number of CPCs in this study cohort. In contrast, Laufs and coworkers elucidated an exercise training–induced increase in CPC number in humans with CAD and in mice 55. These findings are consistent with the hypothesis that exercise training might rejuvenate the damaged vascular tree through CPC mobilization and activation, thereby leading to an enhancement of myocardial perfusion.…”

“…The activation of matrix metalloproteinases 2 and 9 by NO enhances the mobility of CPCs in the bone marrow, resulting in the liberation of these cells into the circulation 42, 52, 53. Furthermore, the number and functional capacity of circulating CPCs seem to depend on NO bioavailibility 53, 54, 55. In response to exercise training, CPCs repaired damaged endothelium, enhanced neoangiogenesis, and reduced neointima formation after vascular injury 1, 55.…”

“…Furthermore, the number and functional capacity of circulating CPCs seem to depend on NO bioavailibility 53, 54, 55. In response to exercise training, CPCs repaired damaged endothelium, enhanced neoangiogenesis, and reduced neointima formation after vascular injury 1, 55. However, their contribution to vascular homeostasis in healthy humans is poorly understood and requires further studies 56…”

“…An elevated apoptotic rate of mature vascular endothelial cells in conjunction with an impaired regenerative capacity of CPC might further aggravate vascular alterations 55, 59, 60. Current knowledge of endothelial dysfunction in vascular disease is discussed in detail by Vanhoutte et al 61…”