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Physical exercise and endothelial progenitor cells.

Increasing evidence has shown that cardiovascular function is significantly modulated by circulating premature cells derived from the bone marrow. A subset of these stem cells named endothelial progenitor cells (EPC) enhances angiogenesis, promotes vascular repair, and improves endothelial function. The circulating numbers and functional properties of EPC are regulated. Vascular risk factors such as smoking, diabetes, and hypertension have been shown to reduce EPC, suggesting that vascular health and repair require increased numbers of this beneficial population of cells. On the other hand, physical activity or lipid lowering with statin drugs can be used to raise EPC numbers and improve their function. Importantly, it was recently shown that reduced levels of circulating EPC represent a cellular marker that independently predicts outcome in patients with vascular disease. Physical activity is associated with a decrease in cardiovascular events and is therefore recommended as a central component of primary and secondary prevention of vascular diseases. Physical training improves endothelial function, exercise capacity, and collateralization in patients with coronary artery disease, chronic heart failure, and peripheral artery disease. However, the molecular effects of physical exercise are only partly understood. Individual advice regarding the duration and intensity of physical exercise remains an important clinical problem, and there is need for novel surrogate parameters to determine the vascular effects of specific training programs. In mice, voluntary running exercise increased EPC numbers by a mechanism related to the bioavailability of nitric oxide because exercise-mediated upregulation of EPC was absent in eNOSj/j animals or in the presence of a nitric oxide synthase inhibitor. In patients with vascular risk factors or established coronary artery disease, numbers and function of EPC are impaired. Indeed, recent data show that EPC increases after exercise-induced ischemia or exhaustive symptom-limited dynamic exercise in these patients. Furthermore, a 4-week exercise program was associated with an up-regulation of circulating CD34+/VEGFR2+ EPC in elderly patients with documented coronary artery disease. In healthy volunteers, intensive and moderate exercising for 30 minutes, but not for 10 minutes, acutely increases circulating levels of EPC. In this issue of Journal of Cardiopulmonary Rehabilitation, Paul et al provide important additional information showing that a 3-month cardiac rehabilitation program powerfully increased CD133+/VEGFR2+ EPC by approximately 2-fold and colony forming units, an important parameter of the replicative potential, by approximately 3-fold. This effect was associated with increased blood nitrite concentrations and reduction of EPC apoptosis. Importantly, these effects were observed in the presence of effective lipid lowering with statin therapy (mean LDL cholesterol, approximately 80 mg/dL). Interestingly, the study identifies a minority of patients who do not respond to the rehabilitation program with an increase in blood nitrite or EPC numbers. The characteristics of this group are not shown in the article, but the authors state in their discussion that they were unable to pinpoint an explanation for this difference. Because this was not a training study, the extent of individual exercise was not quantitated. Future studies will need to test if different modalities of activity exert differential effects on progenitor cells. Furthermore, it cannot be ruled out that the nonexercise interventions during the rehabilitation program (dietary modification and relaxation techniques) may have contributed to the increase in EPC. The key question, however, is whether patients who do not