Exercise-induced expression of angiogenic growth factors in skeletal muscle and in capillaries of healthy and diabetic mice (original) (raw)
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The FASEB Journal, 2006
Diabetes alters microvascular structure and function and is a major risk factor for cardiovascular diseases. In diabetic skeletal muscle, impaired angiogenesis and reduced VEGF-A expression have been observed, whereas in healthy muscle exercise is known to have opposite effects. We studied the effects of type 1 diabetes and combined exercise training on angiogenic mRNA expression and capillarization in mouse skeletal muscle. Microarray and real-time PCR analyses showed that diabetes altered the expression of several genes involved in angiogenesis. For example, levels of proangiogenic VEGF-A, VEGF-B, neuropilin-1, VEGFR-1, and VEGFR-2 were reduced and the levels of antiangiogenic thrombospondin-1 and retinoblastoma like-2 were increased. Exercise training alleviated some of these changes, but could not completely restore them. VEGF-A protein content was also reduced in diabetic muscles. In line with the reduced levels of VEGF-A and other angiogenic factors, and increased levels of angiogenesis inhibitors, capillary-to-muscle fiber ratio was lower in diabetic mice compared to healthy controls. Exercise training could not restore capillarization in diabetic mice. In conclusion, these data illustrate that type 1 diabetes is associated with reduced skeletal muscle capillarization and the dysregulation of complex angiogenesis pathways.-Kivelä, R., Silvennoinen, M., Touvra, A.-M., Lehti, T. M., Kainulainen, H., Vihko, V. Effects of experimental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle. FASEB J. 20, E921-E930 (2006) Key Words: angiogenesis ⅐ hyperglycemia ⅐ growth factor ⅐ VEGF E921 0892-6638/06/0020-0921 © FASEB E922 Vol. 20 June 2006 KIVELÄ ET AL. The FASEB Journal E923 DIABETES, EXERCISE TRAINING, AND ANGIOGENESIS Gene expressions are expressed in relation to the control group at the same time point. Statistically significant changes are color-coded: red ϭ up-regulated (two-based log of ratio (sample/control) Ն0.3 and PՅ0.0025), green ϭ down-regulated (two-based log of ratio (sample/control) Յ-0.3 and PՆ0.9975), yellow ϭ diabetes-induced change in expression was attenuated by exercise (significant change in expression in opposite direction in comparisons DT vs. D and D vs. C). Group abbreviations: D ϭ diabetic, DT ϭ diabetic trained, and T ϭ healthy trained, numbers ϭ time of the treatment in weeks.
AJP: Heart and Circulatory Physiology, 2007
Blood and lymphatic vessels form together the circulatory system allowing the passage of fluids and molecules within the body. Recently we showed that lymphatic capillaries are also found in the capillary bed of skeletal muscle. Exercise is known to induce angiogenesis in skeletal muscle, but it is not known whether exercise has effects on lymphangiogenesis or lymphangiogenic growth factors. We studied lymphatic vessel density and the expression of the main lymphangiogenic growth factors VEGF-C, VEGF-D, and their receptor VEGFR-3 in response to acute running exercise and endurance exercise training in the skeletal muscle of healthy and diabetic mice. VEGF-C mRNA expression increased after the acute exercise bout (P < 0.05) in healthy muscles, but there was no change in diabetic muscles. VEGF-C levels were not changed either in healthy or in diabetic muscle after the exercise training. Neither acute exercise nor exercise training had an effect on the mRNA expression of VEGF-D or VEGFR-3 in healthy or diabetic muscles. Lymphatic vessel density was similar in sedentary and trained mice and was more than 100-fold smaller than blood capillary density. Diabetes increased the mRNA expression of VEGF-D (P < 0.01).
Background: Vascular endothelial growth factor (VEGF) expres- sion is a potent mitogen for endothelial cells that is involved in angiogenesis. Cardiac VEGF is decreased in many pathologic conditions, including diabetes mellitus and aging. Exercise training has improved VEGF expression in the aging heart. Thus, the aim of our study is to illustrate the impact of treadmill exercise training on the cardiac VEGF expression in type I diabetic rats. Methods: Twenty normal Sprague-Dawley rats and Sprague Dawley rats with streptozotocin-induced diabetes were divided into the following equal groups: sedentary control (SC), exercised control (EC), sedentary diabetic rats (SD) and exercised diabetic rats (ED). Immunohistochemistry was used to investigate VEGF expression in the cardiac tissue in each of the four different groups. Results: Cardiac VEGF expression was significantly (P < 0.05) lower in SD compared with that in SC. However, exercise training significantly (P < 0.01) enhanced VEGF expression in the cardiac tissue in ED compared with that in SD. Conclusion: Our present data suggest that treadmill exercise training improved diabetes-induced downregulation in the cardiac VEGF expression.
Angiogenic growth factor responses to long-term treadmill exercise in mice
Indian journal of physiology and pharmacology
We sought to determine whether VEGF and other angiogenic growth factors and their receptors might be subject to negative feedback regulation during two weeks of treadmill-exercise conditioning in inbred strains of mice. C57BL/6 mice exhibited greater VEGF mRNA and protein responses in gastrocnemius muscle to a single bout of treadmill exercise compared to BALB/c mice. The patterns of VEGF, VEGFR1, VEGFR2, Ang2 and Tie2 mRNA expression in gastrocnemius muscles of C57BL/6 mice during long-term exercise support the hypothesis that they may be subject to negative feedback regulation. The combination of expression patterns for growth factors and their receptors suggests that multiple layers of control mechanisms may exist to prevent angiogenesis following a single bout of exercise and to promote angiogenesis following long-term exercise.
Biomolecules, 2021
Exercise can ameliorate cardiovascular dysfunctions in the diabetes condition, but its precise molecular mechanisms have not been entirely understood. The aim of the present study was to determine the impact of endurance training on expression of angiogenesis-related genes in cardiac tissue of diabetic rats. Thirty adults male Wistar rats were randomly divided into three groups (N = 10) including diabetic training (DT), sedentary diabetes (SD), and sedentary healthy (SH), in which diabetes was induced by a single dose of streptozotocin (50 mg/kg). Endurance training (ET) with moderate-intensity was performed on a motorized treadmill for six weeks. Training duration and treadmill speed were increased during five weeks, but they were kept constant at the final week, and slope was zero at all stages. Real-time polymerase chain reaction (RT-PCR) analysis was used to measure the expression of myocyte enhancer factor-2C (MEF2C), histone deacetylase-4 (HDAC4) and Calmodulin-dependent prote...
Pathophysiology, 1996
The purpose of the present study was to investigate the effect of a single bout of exercise on the capillary growth in an in vitro angiogenesis model and its mechanism. The exercised rats were made to run continuously for 90 min at 20 m/min (0 ° incline) on a rodent treadmill just before sacrifice. First, we investigated the effect of soleus extracts on the capillary growth in an in vitro angiogenesis model based on the co-culture of rat interstitial cells (like smooth muscle cell) (RSMC) and bovine capillary endothelial cells (BCEC). The extracts of soleus muscle from acutely-exercised rats had higher angiogenic activity, compared with those from control rats. The expression of bFGF mRNA in soleus muscle from acutely-exercised rats was also significantly higher than in that from control rats. Next, we found that norepinephrine (NE) at the concentration of 10 .8 to 10-5 M enhanced the capillary growth in the angiogenesis model. Furthermore, the addition of 10-7 M NE markedly enhanced the expression of bFGF mRNA in RSMC, but not in BCEC. The data obtained here suggest that the increased level of NE with physical exercise upregulates the expression of bFGF in satellite cells like RSMC, probably leading to the increased capillarization in skeletal muscle.
Metabolic regulation of exercise-induced angiogenesis
Vascular Biology
Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. Muscle angiogenesis can occur via sprouting and splitting angiogenesis, and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional co-activator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation o...