Expression Pattern of Angiogenic Factors in Healthy Heart in Response to Physical Exercise Intensity

Recently, many studies showing the regeneration potential of both cardiac and hematopoietic stem cells in adult heart following injury were definitively retracted by the literature. Therefore, stimulating myocardial angiogenesis becomes to be important for preventing cardiovascular diseases. Regular endurance exercise has been reported to induce capillary growth in healthy and diseased myocardium resulting in cardioprotective phenotype. Previously, we demonstrated a significantly increased capillary proliferation in mouse hearts following 30 and 45 days of endurance training. In the present study, we examined the localization and expression pattern of vascular endothelial growth factor receptors (VEGFR-1/Flt-1 and VEGFR-2/Flk-1), hypoxia-inducible factor-1α (HIF-1α), and inducible nitric oxide synthase (iNOS) in heart neocapillarization in response to a mild, moderate, and high intensity of endurance training. Sixty-three Swiss male mice were divided into four untrained control groups and three groups trained for 15 (T15), 30 (T30), and 45 (T45) days with a gradually increasing intensity on a treadmill. We observed the localization of studied proteins with immunostaining and their expression level with Western blot analyses. We found that VEGFR-2/Flk-1 expression progressively increased in trained groups compared with controls, while VEGFR-1/Flt-1 and HIF-1α were higher in T15 than in controls, T30, and T45 animals. Differently, iNOS levels enhanced after 15 and 30 days of exercise. The localization of these factors was not altered by exercise. The results showed that the expression of VEGFR-1/Flt-1, VEGFR-2/Flk-1, HIF-1α, and iNOS is differently regulated in cardiac angiogenesis according to the exercise intensity. VEGFR-1/Flt-1 and HIF-1α are upregulated by a mild intensity exercise, while VEGFR-2/Flk-1 progressively enhances with increasing workload. Differently, iNOS protein is modulated by a moderate intensity exercise. VEGF pathway appears to be involved in exercise-related angiogenesis in heart and VEGF might act in a paracrine and endocrine manner. Understanding this relationship is important for developing exercise strategies to protect the heart by insults.