Exercise- induced endothelial repair: the role of stem cells

Endothelial progenitor cells (EPCs) were first isolated from adult peripheral blood and were shown to derive from bone marrow and to incorporate into foci of physiological and pathological neovascularization. Similarly to EPCs, mesenchymal stem cells (MSCs) also possess the potential of vascular regeneration. Both EPCs and MSCs are mobilized from the bone marrow in response to exercise, ischemia and neurohormonal factors such as VEGF, placental growth factor) and critically contribute to maintaining the integrity of the endothelial cell layer.

EPC number and function correlate with the number of cardiovascular risk factors and disease severity as well as predict cardiovascular events and death from cardiovascular causes. In patients with vascular risk factors or established coronary artery disease, numbers and function of EPC are impaired (Vasa, Fichtlscherer et al. 2001).

The regular practice of physical exercise contributes to an approximate 30% reduction in mortality due to cardiovascular diseases. Because the reduction in classical cardiometabolic risk factors, such as hyperlipidemia, hypertension and insulin resistance, explains only approximately 40% of the exercise-induced reduction in mortality, variables directly related to the endothelium could explain why and how physical exercise prevents and decreases the progression of disease, and reduces cardiovascular mortality. One of the possible mechanisms involved in that process is EPC mobilization to peripheral blood.

The principal mechanism of EPC mobilization from the bone marrow seems to depend on the activation of eNOS in the presence of several mobilizing factors. Exercise- induced laminar stress results in an activation of eNOS and resulting in an increase of NO. Afterwards, matrix metalloproteinase-9 (MMP-9) and MMP-2 are activated, resulting in the release of SKitL, which confers signals enhancing mobility of circulating progenitor cells. Subsequently, the circulating progenitor cells are mobilized into the peripheral circulation.

In several studies, it was demonstrated that exercise increases the concentration of NO, which in turn can activate MMP-9 in bone marrow, leading to enhanced mobilization of progenitor cells (Iwakura, Shastry et al. 2006).

Laufs et al. demonstrated that 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 (Laufs, Werner et al. 2004).

Fernandes et al. documented that the number and function of EPCs are repaired after 10 weeks of exercise training in hypertension animal model. Exercise training normalized the EPC levels and function accompanied by an increase in VEGF and NO levels. Their results suggest that this mechanism may be a potential therapeutic application in vascular diseases (Fernandes, Nakamuta et al. 2012).