Abstract
It is well established that acute exercise promotes an angiogenic response and that a period of exercise training results in capillary growth. Skeletal muscle angiogenesis is a complex process that requires a coordinated interplay of multiple factors and compounds to ensure proper vascular function. The angiogenic process is initiated through changes in mechanical and/or metabolic factors during exercise and when exercise is repeated these stimuli may result in capillary growth if needed. The present PhD thesis is based on six studies in which the regulation of angiogenesis in skeletal muscle was investigated. This was achieved by investigating the response of pro-angiogenic and angiostatic factors during acute passive movement and active exercise and during passive and active training. In addition, the response of pro-angiogenic and angiostatic factors during acute passive movement and active exercise was studied in peripheral arterial disease. Vascular endothelial growth factor (VEGF) is the most important factor in exercise-induced angiogenesis and is located primarily in muscle cells but also in endothelial cells, pericytes, and in the extracellular matrix. VEGF protein secretion to the interstitium is increased upon muscle contraction in an all or
nothing response. However, the subcelluar localization of VEGF and the mechanisms underlying the exerciseinduced secretion of VEGF have not been elucidated. Investigation of the subcellular localization of VEGF revealed the novel finding of VEGF containing vesicles located just beneath the sarcolemma and between contractile elements of the muscle fibres. In addition,the observation of an increase in VEGF containing vesicles just beneath the skeletal muscle membrane in response to an acute bout of exercise points to intracellular translocation of VEGF vesicles being a mechanism for regulating VEGF secretion in response to exercise. Furthermore, the exercise-induced increase in VEGF secretion was shown to be mediated in part through adenosine which is released during contraction, and its receptor A2B which activates the MAPK pathway and in part through activation of the PKA pathway independent of adenosine. The secretion of VEGF from the muscle during an acute bout of exercise was not found to significantly reduce tissue levels of VEGF, probably due to the large stores of VEGF within the myocytes. VEGF protein secretion increases similarly during acute exercise and passive movement before and after training which appears to be independent of exercise intensity at sub-maximal levels whereas high intensity exercise results in a lower increase in the interstitial VEGF protein concentration. The reason for a lower increase in interstitial VEGF with high intensity exercise is unclear but it seems likely that VEGF secretion is inhibited by a negative regulation mechanism during high intensity exercise.
The complex process of trainig-induced angiogenesis is regulated through a number of different factors of which VEGF appears to be the most important. Furthermore, it appears that the pro-angiogeinc factors, eNOS, MMP9, Ang2, and Tie-2 and the angiostatic factors, TIMP-1 and TSP-1 play an important part in modulation the angiogenic response to acute exercise and training in human skeletal muscle thus determining if capillary growth occurs or not.
The lack of increase in VEGF secretion in peripheral arterial disease patients in response to acute passive movement and active exercise points to an impairment in the regulation of exercise-induced VEGF secretion as the basal interstitial VEGF concentration was similar to age matched healthy control individuals and similar in magnitude to young individuals. Furthermore, the limited response to acute passive movement and active exercise in PAD patients was similar to aged matched control individuals, however, the higher interstitial TSP-1 protein concentration in PAD patients indicate that the angiogenic potential in response to exercise and training is limited in these patients. The capillarization level was lower in individuals with peripheral arterial disease than in matched control individuals. Thus it appears that ageing is a more prominent factor than peripheral arterial disease for the angiogenic response to exercise in skeletal muscle cells whereas disease is a more determining factor for the capillary network.
In conclusion, the findings in the six studies that the PhD thesis is based on provide valuable information to further the understanding of the regulation of human skeletal muscle angiogenesis. The novel finding of VEGF containing vesicles localized close to the muscle cell membrane and between the contractile elements of the muscle cell and the proposed mechanism for intracellular translocation in response to acute exercise adds new knowledge into the regulation of VEGF secretion. Furthermore, the findings of simultaneously enhanced pro-angiogenic and angiostatic factors in response to acute exercise before training points to that the angiogenic process is highly regulated even when capillary growth is required. The attenuated response in some of the pro-angiogenic factors after training and a concurrent increase in the angiostatic factors occur when capillary growth no longer is required. Thus the balance of pro-angiogenic and angiostatic factors is a determining regulator of exercise-induced angiogenesis in human skeletal muscle.
nothing response. However, the subcelluar localization of VEGF and the mechanisms underlying the exerciseinduced secretion of VEGF have not been elucidated. Investigation of the subcellular localization of VEGF revealed the novel finding of VEGF containing vesicles located just beneath the sarcolemma and between contractile elements of the muscle fibres. In addition,the observation of an increase in VEGF containing vesicles just beneath the skeletal muscle membrane in response to an acute bout of exercise points to intracellular translocation of VEGF vesicles being a mechanism for regulating VEGF secretion in response to exercise. Furthermore, the exercise-induced increase in VEGF secretion was shown to be mediated in part through adenosine which is released during contraction, and its receptor A2B which activates the MAPK pathway and in part through activation of the PKA pathway independent of adenosine. The secretion of VEGF from the muscle during an acute bout of exercise was not found to significantly reduce tissue levels of VEGF, probably due to the large stores of VEGF within the myocytes. VEGF protein secretion increases similarly during acute exercise and passive movement before and after training which appears to be independent of exercise intensity at sub-maximal levels whereas high intensity exercise results in a lower increase in the interstitial VEGF protein concentration. The reason for a lower increase in interstitial VEGF with high intensity exercise is unclear but it seems likely that VEGF secretion is inhibited by a negative regulation mechanism during high intensity exercise.
The complex process of trainig-induced angiogenesis is regulated through a number of different factors of which VEGF appears to be the most important. Furthermore, it appears that the pro-angiogeinc factors, eNOS, MMP9, Ang2, and Tie-2 and the angiostatic factors, TIMP-1 and TSP-1 play an important part in modulation the angiogenic response to acute exercise and training in human skeletal muscle thus determining if capillary growth occurs or not.
The lack of increase in VEGF secretion in peripheral arterial disease patients in response to acute passive movement and active exercise points to an impairment in the regulation of exercise-induced VEGF secretion as the basal interstitial VEGF concentration was similar to age matched healthy control individuals and similar in magnitude to young individuals. Furthermore, the limited response to acute passive movement and active exercise in PAD patients was similar to aged matched control individuals, however, the higher interstitial TSP-1 protein concentration in PAD patients indicate that the angiogenic potential in response to exercise and training is limited in these patients. The capillarization level was lower in individuals with peripheral arterial disease than in matched control individuals. Thus it appears that ageing is a more prominent factor than peripheral arterial disease for the angiogenic response to exercise in skeletal muscle cells whereas disease is a more determining factor for the capillary network.
In conclusion, the findings in the six studies that the PhD thesis is based on provide valuable information to further the understanding of the regulation of human skeletal muscle angiogenesis. The novel finding of VEGF containing vesicles localized close to the muscle cell membrane and between the contractile elements of the muscle cell and the proposed mechanism for intracellular translocation in response to acute exercise adds new knowledge into the regulation of VEGF secretion. Furthermore, the findings of simultaneously enhanced pro-angiogenic and angiostatic factors in response to acute exercise before training points to that the angiogenic process is highly regulated even when capillary growth is required. The attenuated response in some of the pro-angiogenic factors after training and a concurrent increase in the angiostatic factors occur when capillary growth no longer is required. Thus the balance of pro-angiogenic and angiostatic factors is a determining regulator of exercise-induced angiogenesis in human skeletal muscle.
| Original language | English |
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| Publisher | Department of Nutrition, Exercise and Sports, Faculty of Sciences, University of Copenhagen |
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| Number of pages | 192 |
| ISBN (Print) | 978-87-7611-571-5 |
| Publication status | Published - 2013 |
