Endothelial cell integrity is essential for maintaining proper vessel function and preserving vascular homeostasis . Endothelial dysfunction has been found in numerous pathologies including hypertension, diabetes, chronic kidney disease, and in all stages of atherosclerosis . This is an early event in vascular disease that frequently precedes cardiovascular complications [1–3] and is associated with cardiovascular risk and mortality. Experimental and clinical studies have shown that endothelial dysfunction and low-grade vascular inflammation play a key role in the development of coronary artery disease (CAD) [1–3], which remains the main cause of mortality in developed countries. Several markers of endothelial function have been assessed, among those, bone marrow-derived endothelial progenitor cells (EPCs) have been studied as novel biomarkers to measure the severity of cardiovascular diseases. Moreover, EPC is thought of as a potential new strategy in regenerative medicine in several cardiovascular conditions (i.e. IMA, cardiomiopathies, peripheral arterial occlusive disease) . EPCs are small, immature precursor cells that are detectable also in plasma other that bone marrow . However, there is a debate whether these cells represent a structurally and functionally homogeneous cell population . EPCs in the peripheral circulation are capable of differentiating into mature endothelial cells and thereby repairing the damaged endothelial cell layer . Thus, reduction in EPC may contribute to the development of endothelial dysfunction. In this regard, the EPC levels and colony-forming capacity correlated with measures of endothelial function (such as flow-mediated vasodilation) in clinical studies [2,7].
The importance of EPC is supported by the observation that EPC number and function correlate with cardiovascular risk factors  and also predict cardiovascular events and death . It has been shown that the amount and function of EPC is significantly impaired in different physiological and pathological conditions including aging, diabetes, hypertension, hypercholesterolemia, and chronic kidney disease [10,11]. This occurs mainly for cellular senescence and proinflammatory cytokines-induced impairment of cell proliferation . In particular, in patients with CAD, reduced plasma EPC levels correlate with increased risk of cardiovascular morbidity and mortality .
Several therapeutic strategies including statins, antihypertensive drugs, or physical exercise reduce cardiovascular risk and improve endothelial dysfunction and inflammation [2,3,13]. In particular, clinical and experimental studies have shown that physical exercise is a powerful tool to positively influence the development and progression of atherosclerosis and CAD. The vascular effects of chronic exercise may include structural and functional adaptations. In particular, physical activity may restore normal endothelial structure and function , and promote angiogenesis that may explain, in part, the association between physical activity and reduced cardiovascular events [11,14]. However, the mechanisms by which exercise improves endothelial function in patients with CAD are not fully clarified. Exercise training decreases proinflammatory cytokine production and increase nitric oxide (NO) bioavailability, antioxidant defences, as well as the regenerative capacity of endothelium by improving the EPC number [13,14]. Exercise bout and exercise training program can mobilize EPCs from the bone marrow by different mechanisms. Exercise training may increase vascular shear stress and enhance the NO-induced matrix metalloproteinase 9 within the bone marrow  through the activation of PI3K/Akt/eNOS pathway . Conversely, an acute exercise bout increases genes transcription including the proliferator-activated receptor gamma coactivator-1 alpha and hypoxia-inducible factor-1 . These molecules, in turn, induce the expression of growth factors (i.e. vascular endothelial growth factor, stromal cell-derived factor-1, erythropoietin), which are key regulators of EPC mobilization [18,19]. It must be noted that the amount of circulating EPCs after a single exercise bout quickly declines to baseline values in a short period . On the contrary, regular physical activity may increase circulating EPC levels for a longer period .
Once in the circulation EPCs may participate in the maintenance of the endothelial cell layer and contribute to the neoangiogenic process. It has been shown that EPCs may contribute to neoangiogenesis  in animal models and to the formation of new blood vessels, contributing to the recovery of the ischemic tissue . In this regard, the study from Fernandes et al. published in the current issue of the Journal confirms and extends these findings providing evidence that exercise training may restore EPC impairment in hypertension which represent one of the major risk factors for CAD. Moreover, this study also showed that exercise training may correct microvascular rarefaction in spontaneously hypertensive rats, suggesting that exercise training may prevent the microvascular abnormalities and the vascular regenerative potential in hypertensive patients.
However, it is uncertain whether the mobilization of EPCs induced by exercise training is closely related to the improvement of endothelial function. Indeed, it is not clear whether the circulating EPC may participate in endothelial cell repair by differentiating into mature endothelial cells or through the stimulation of mature endothelial cells to proliferate via paracrine mechanisms [9,11,13,14]. Therefore, further studies are required to clarify whether the mobilization of EPCs and the improvement in endothelial function are directly related, or represent distinct observations during the exercise training program.
Furthermore, the mechanism by which EPCs contribute to the repair of endothelium in cardiovascular disease is not fully understood and future experiments should be performed in order to clarify whether EPCs mobilization is relevant for the improvement of endothelial function in patients with cardiovascular disease particularly during exercise training.
Conflicts of interest
There are no conflicts of interest.
1. Savoia C, Schiffrin EL. Inhibition of the renin angiotensin system: implications for the endothelium. Curr Diab Rep
2. Burger D, Touyz RM. Cellular biomarkers of endothelial health: microparticles, endothelial progenitor cells, and circulating endothelial cells. J Am Soc Hypertens
3. Savoia C, Schiffirn EL. Inflammation in hypertension. Curr Opin Nephrol Hypertens
4. Sen S, McDonald SP, Coates PT, Bonder CS. Endothelial progenitor cells: novel biomarker and promising cell therapy for cardiovascular disease. Clin Sci
5. Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol
6. Urbich C, Dimmeler S. Endothelial progenitor cells. Characterization and role in vascular biology. Circ Res
7. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med
8. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res
9. Mobius-Winkler S, Hollriegel R, Schuler G, Adams V. Endothelial progenitor cells: implications for cardiovascular disease. Cytometry
10. Heiss C, Keymel S, Niesler U, Ziemann J, Kelm M, Kalka C. Impaired progenitor cell activity in agerelated endothelial dysfunction. J Am Coll Cardiol
11. Lenk K, Uhlemann M, Schuler G, Adams V. Role of endothelial progenitor cells in the beneficial effects of physical exercise on atherosclerosis and coronary artery disease. J Appl Physiol
12. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med
13. Ribeiro F, Alves AJ, Duarte JA, Oliveira J. Is exercise training an effective therapy targeting endothelial dysfunction and vascular wall inflammation? Int J Cardiol
14. Padilla J, Simmons GH, Bender SB, Arce-Esquivel AA, Whyte JJ, Laughlin MH. Vascular Effects of Exercise: Endothelial Adaptations Beyond Active Muscle Beds. Physiology (Bethesda)
15. Iwakura A, Shastry S, Luedemann C, Hamada H, Kawamoto A, Kishore R, et al. Estradiol enhances recovery after myocardial infarction by augmenting incorporation of bone marrow-derived endothelial progenitor cells into sites of ischemia-induced neovascularization via endothelial nitric oxide synthase-mediated activation of matrix metalloproteinase-9. Circulation
16. Laufs U, Werner N, Link A, Endres M, Wassmann S, Jürgens K, et al. Physical training increases endothelial progenitor cells, inhibition of neointima formation, and enhances angiogenesis. Circulation
17. Lundby C, Gassmann M, Pilegaard H. Regular endurance training reduces the exercise induced HIF-1alpha and HIF-2alpha mRNA expression in human skeletal muscle in normoxic conditions. Eur J Appl Physiol
18. Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, et al. Erythropoietin is a potent physiological stimulus for endothelial progenitor cell mobilization. Blood
19. Asahara T, Takahashi T, Masuda H. VEGF contributes to postata neovascularization by mobilizing bone-marrow endothelial progenitor cells. EMBO J
20. Möbius-Winkler S, Hilberg T, Menzel K, Golla E, Burman A, Schuler G, Adams V. Time-dependent mobilization of circulating progenitor cells during strenuous exercise in healthy individuals. J Appl Physiol
21. Sandri M, Adams V, Gielen S, Linke A, Lenk K, Krankel N, et al. Effects of exercise and ischemia on mobilization and functional activation of bloodderived progenitor cells in patients with ischemic syndromes: results of 3 randomized studies. Circulation
22. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angioneogenesis. Science
23. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med
24. Fernandes T, Nakamuta JS, Magalhães FC, Roque FR, Lavini-Ramos C, Schettert IT et al.
Exercise training restores the endothelial progenitor cells number and function in hypertension: implications for angiogenesis. J Hypertens