Abstract
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.
Highlights
Regular physical exercise is well known to reduce cardiovascular diseases, the main cause of death worldwide, increasing cardiac function and protecting against myocardial damage (Schuler et al, 2013; Tao et al, 2015)
We carried out this study using the same samples of heart prepared in our previous studies, in which we detected left ventricle hypertrophy associated with a significant increase in the capillary proliferation after 30 and 45 days of endurance training (Bellafiore et al, 2007, 2013)
We examined the relationship between VEGFR-1/ Flt-1, VEGFR-2/Flk-1, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS) expression and angiogenesis in heart in response to low, moderate, and high exercise intensity
Summary
Regular physical exercise is well known to reduce cardiovascular diseases, the main cause of death worldwide, increasing cardiac function and protecting against myocardial damage (Schuler et al, 2013; Tao et al, 2015). Modifications in the blood flow, muscle contraction, and oxygen levels associated with hemodynamic mechanical events have been shown to be key signals for triggering vessel wall remodeling and activation of growth factors involved in the proliferation, migration, and tube formation of endothelial cells in both heart and skeletal muscle (Brown, 2003; Prior et al, 2004). This implies a cross talk between skeletal and cardiac muscle in order to respond synergistically to various stimuli derived by physical exercise. Several studies recently reported that exercise stimulates the release of circulating cytokines and growth factors, called myokines, by skeletal muscle that acts with endocrine functions mediating exercise-induced cardiovascular adaptations (Giudice and Taylor, 2017; Hoffmann and Weigert, 2017)
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