1. Custodis, Florian
  2. Laufs, Ulrich

Article Content

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.1-3 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.4,5 On the other hand, physical activity or lipid lowering with statin drugs can be used to raise EPC numbers and improve their function.1,4-6 Importantly, it was recently shown that reduced levels of circulating EPC represent a cellular marker that independently predicts outcome in patients with vascular disease.7


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,8-10 chronic heart failure,11 and peripheral artery disease.12 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 up-regulation of EPC was absent in eNOS-/- animals or in the presence of a nitric oxide synthase inhibitor.6 In patients with vascular risk factors or established coronary artery disease, numbers and function of EPC are impaired.13 Indeed, recent data show that EPC increases after exercise-induced ischemia or exhaustive symptom-limited dynamic exercise in these patients.5,14 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.6 In healthy volunteers, intensive and moderate exercising for 30 minutes, but not for 10 minutes, acutely increases circulating levels of EPC.15 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).1,4 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 respond to preventive lifestyle changes with an increase in EPC numbers exhibit an increased risk of subsequent cardiovascular events. The EPCAD study has demonstrated the association of EPC numbers with outcome in patients with coronary disease.7 Further studies need to show if the extent of EPC increase by therapeutic interventions, such as exercising, predicts cardiovascular morbidity.


Prospective clinical trials quantitating the vasculoprotective effects of exercise are rare. Therefore, individual recommendations regarding the intensity and duration of are difficult. For most vascular risk factors, validated surrogate parameters are available, such as blood pressure for hypertension, or serum lipid and glucose levels for hypercholesterolemia and diabetes. However, few parameters are available to assess the efficacy of vascular protection of an individual exercise training program. It would be helpful to use a blood test to compare different training modalities and to advice patients regarding treatment goals. Quantification of EPC may provide a novel surrogate parameter and tool to foster the study and the clinical use of exercise for the prevention of cardiovascular disease. An important step toward this goal is the search for easier and more widely applicable methods of EPC measurements.


Despite extensive epidemiological data demonstrating a variety of beneficial effects of exercise, relatively little is known about the underlying molecular mechanism(s).8,11,12,16 The study of Paul et al provides novel and convincing support of the concept that up-regulation of EPC represents an important beneficial mechanism of physical training. In addition to the protective effects of EPC on the vasculature, recent data suggest that EPC may have the potential to trans-differentiate, for example, into functionally active cardiomyocytes.17 Therefore, it is interesting to speculate that exercise-mediated regulation of adult stem cells may not be limited to EPCs but may be important beyond cardiovascular medicine.




1. Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001;108:391-397. [Context Link]


2. Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003;9:1370-1376. [Context Link]


3. Werner N, Junk S, Laufs U, et al. Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res. 2003;93:e17-e24. [Context Link]


4. Werner N, Priller J, Laufs U, et al. Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol. 2002;22:1567-1572. [Context Link]


5. Adams V, Lenk K, Linke A, et al. Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia. Arterioscler Thromb Vasc Biol. 2004;24:684-690. [Context Link]


6. Laufs U, Werner N, Link A, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation. 2004;109:220-226. [Context Link]


7. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999-1007. [Context Link]


8. Belardinelli R, Paolini I, Cianci G, Piva R, Georgiou D, Purcaro A. Exercise training intervention after coronary angioplasty: the ETICA trial. J Am Coll Cardiol. 2001;37:1891-1900. [Context Link]


9. Hambrecht R, Walther C, Mobius-Winkler S, et al. Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: a randomized trial. Circulation. 2004;109:1371-1378. [Context Link]


10. Endres M, Gertz K, Lindauer U, et al. Mechanisms of stroke protection by physical activity. Ann Neurol. 2003;54:582-590. [Context Link]


11. Hambrecht R, Fiehn E, Weigl C, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation. 1998;98:2709-2715. [Context Link]


12. Stewart KJ, Hiatt WR, Regensteiner JG, Hirsch AT. Exercise training for claudication. N Engl J Med. 2002;347:1941-1951. [Context Link]


13. Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001;89:E1-E7. [Context Link]


14. Rehman J, Li J, Parvathaneni L, et al. Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells. J Am Coll Cardiol. 2004;43:2314-2318. [Context Link]


15. Laufs U, Urhausen A, Werner N, et al. Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects. Eur J Cardiovasc Prev Rehabil. 2005;12:407-414. [Context Link]


16. Laufs U, Wassmann S, Czech T, et al. Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25:809-814. [Context Link]


17. Badorff C, Brandes RP, Popp R, et al. Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation. 2003;107:1024-1032. [Context Link]