Laufs et al[101
] in 2004 were the first research group to demonstrate that physical activity leads to an increased number of circulating EPCs in mice after 28 wk of running wheels. This effect occurred rapidly (7 d after training) and was sustained for at least 4 wk, providing evidence that EPC numbers can be increased by nearly threefold by exercise training. These findings were confirmed by another research group in a human study in which middle aged and older subjects following a 3 mo training program of walking, at moderate intensity, increased circulating angiogenic cell (CAC) migratory capacity by 50%[20
]. Accordingly, Yang et al[102
] showed that the number and activity of circulating EPCs of 10 older and 10 young sedentary healthy men were increased after 3 mo regular exercise. However, the increased number and activity of circulating EPCs of older sedentary healthy men was higher compared to the younger group. In contrast, in a study of 20 healthy men who followed a 6-wk interval exercise training program, [moderate (9 subjects) or high intensity (11 subjects)], there was no significant effect on EPC number in both groups, even though there was an improvement of vasoconstrictor function[103
Furthermore, a study of 182 children (aged 11.1 ± 0.7 years) showed that physical activity by means of daily school exercise lessons can increase the number of circulating progenitor cells[104
]. More interestingly, EPC numbers decreased significantly after 10 d of detraining in highly active older men, even lower than the level of low-active (sedentary) men[105
]. These findings agree with the fact that sustained physical activity is necessary to preserve improved endothelial function for maintaining long-term training effects[106
In an animal study, 8 wk of aerobic training in mice with advanced atherosclerotic lesions showed no improvement in atherosclerosis, whereas mice with early lesions benefited. The authors suggest that the impact of exercise on atherogenesis is primarily to retard the progression to advanced lesions, rather than reversing advanced lesions. Interestingly, the level of EPCs decreased, along with proinflammatory cytokines in response to exercise[107
In another experimental study conducted in the early phase following traumatic brain injury in rats, the exercise group compared to the control group enhanced significantly proliferation of neural stem cells (NSCs) around the damaged area[108
Despite the significant experimental study of Laufs et al[101
], Luk et al[109
] showed that there was no significant increase in CD34/KDR+
EPCs after an 8-wk exercise training programme on 32 patients with CAD compared to controls. In contrast, in a recent uncontrolled study by Cesari et al[110
], there was a significant increase in EPCs and a significant decrease in proinflammatory biomarkers, in patients with acute coronary syndrome, occurring after a 30-d period of cardiac rehabilitation (3 sessions per week of endurance training on a cycle ergometer, at 60%-70% of individual VO2
level obtained at peak exercise during baseline symptom-limited cardiopulmonary exercise testing). Because of the conflicting results and the small number of studies, more human studies are needed to clarify the possible beneficial effects of exercise on EPCs in CAD.
EPC levels [assessed as CD34+
cells coexpressing AC133 and vascular endothelial growth factor receptor 2 (VEGFR2), and as endothelial CFUs (e-CFUs)] were also evaluated in chronic renal failure patients on hemodialysis after a 6-mo walking exercise program. This study showed that there was not a significant change in CD34+
cell numbers, but there was a significant change in e-CFUs[111
A significant enhancement of circulating EPCs after 8 wk of supervised exercise training has also been demonstrated in CHF patients. In that study, 8 wk of detraining led to baseline EPC levels[112
]. In a recent study by Van Craenenbroeck et al[113
] similar results have emerged after investigating the effect of 6 mo exercise training in CHF, compared with a no exercise CHF group and a no exercise group of healthy subjects. The authors reported a reverse effect of exercise training on circulating angiogenic cell dysfunction and an increase in EPCs. An analogous increase in EPC numbers was found, after short-term exercise training (3 wk) in 14 CHF patients[114
]. The exercise program was a combination of calisthenics and aerobic exercise with an intensity up to 75%-85% of the maximum heart rate attained in the exercise test. The authors reported that even a relatively short-term exercise training program significantly improved the serum ability to support viability of EPCs as well as upregulation of proteins participating in LV remodeling.
Similarly, 37 CHF patients (LV ejection fraction 24% ± 2%) were randomly assigned to 12 wk of exercise training (n
= 18) or sedentary lifestyle (n
= 19). Exercise training increased the number of CD34+
progenitor cells from 1094 ± 677 to 1450 ± 798 cells/mL blood in the training group (P
= 0.032 vs
control). The number of CD34+
EPCs was found to be augmented from 100 ± 127 to 183 ± 156 cells (P
= 0.014 vs
control) and their migratory capacity by 224 ± 263 vs
-12 ± 159 CPCs/1000 plated CPCs in controls (P
The most recent paper on the effect of exercise training in patients with CHF is the one published by Mezzani et al[116
]. Patients (n
= 30) with NYHA class II were allocated to either an aerobic 3-mo exercise training group or a control group, while seven age-matched healthy subjects were also studied. In addition to the previous studies, the authors reported that the numbers of EPCs, even though they did not differ between patient groups at baseline, significantly increased in the CHF training group, reaching values similar to those of healthy controls, while the difference between CHF controls and healthy controls did not reach statistical significance. Additionally, the levels of EPCs remained unchanged in the control patient group.
In a randomized controlled clinical trial, 40 patients with PAD were allocated to either an exercise or a control group. The intervention group followed a standardized training program twice a week for 6 mo. The initial duration included 35 min of intermittent walking, which was increased by 5 min each session until 50 min of intermittent walking was achieved. EPC levels were significantly increased and asymmetric dimethylarginine levels were decreased in the exercise group compared with the controls. The authors suggested an enhanced angiogenesis and improved endothelial function that might contribute to cardiovascular risk reduction[117
The first study on the effect of exercise training in overweight and obese patients has recently been published by Cesari et al[118
]. Even though the study had a few methodological limitations, the authors reported a significant increase in all the three groups of EPCs (CD34+
: +33.3%; CD133/KDR+
: +35%; CD34+
: +35.7%) after a 3 mo exercise intervention program, compared to baseline measurements.
The underlying mechanisms of the effect of exercise training on EPC levels needs further investigation, but taken together with the existing data, it has been suggested that physical exercise increases NO bioavailability[119
], and in parallel with this fact, the effect of physical activity on EPCs is markedly reduced after inhibition or deletion of eNOS, which suggests an NO-dependent increase in EPCs in response to exercise[101
]. Additionally, it has been reported that physical exercise may increase EPC numbers by prolonging their lifespan. Data derived from cultured EPCs have indicated that the observed EPCs enhancement in the circulation and the bone marrow could be explained partly by antiapoptotic effects of physical activity on EPCs and potentially their progeny[101
]. The extra muscle stress that is additive to hypoxic stress and leads to a hypoxia-induced factor-1-mediated upregulation of both VEGF and stromal-cell-derived factor (SDF)-1 stimulated EPCs mobilization, as demonstrated by Sarto et al[112
Even though the studies mentioned above followed different methodologies and exercise training protocols, we may assume that regular exercise training increases significantly circulating EPC levels, both in healthy subjects (rodents and humans) and in a variety of diseases. The strongest evidence so far in cardiovascular disease emerges from studies in CHF and PAD. More data are needed, however, to confirm the results of these preliminary studies and to investigate the optimum exercise protocol in order to maximize the possible beneficial effects.
Summaries of the long-term exercise training effects on EPCs in animals and healthy subjects as well in disease populations are illustrated in Tables and , respectively.
Effects of exercise training on endothelial progenitor cells in animals and healthy subjects
Effects of exercise training on endothelial progenitor cells in different disease populations