Abstract
Cardiovascular health in aged subjects and the effects of physical activity and resveratrol Aging and inactivity are associated with decreased physical capacity and cardiovascular
health, which ultimately, may affect quality of life. However, the findings of the present thesis
support that even a relatively short period of exercise training improves a number of
cardiovascular health parameters and increases exercise capacity in previously sedentary
aged men. In contrast, our findings show that, although resveratrol has shown promising
results in terms of improving cardiovascular health and physical capacity in animal models,
this does not appear to be true in aged individuals. Moreover, resveratrol blunted a number of
positive adaptations related to physical activity, including blood pressure, physical capacity
and other cardiovascular health factors.
Physical activity, resveratrol and endogenous antioxidants In aged individuals, the presence of ROS may be excessive, due to increased ROS formation and reduced antioxidant defense capacity. Such an increase in oxidative stress could lead to cell damage and inflammation. The present work shows that a period of exercise training in aged men can lower markers of basal oxidative stress and inflammation in skeletal muscle. The effect of training on markers of oxidative stress was likely, at least in part, due to a increase in skeletal muscle levels of SOD2, as the potential for ROS formation actually increased as evidenced by an increase in the expression of NAD(P)H oxidase. This latter finding of a training induced increase in NAD(P)H oxidase emphasizes the importance of ROS for muscle function and adaptation and to some extent even questions the theory of harmful oxidative stress in healthy aged individuals. Our studies were not able to support a positive effect of resveratrol supplementation on markers of oxidative stress or inflammation in aged individuals. In contrast, resveratrol supplementation actually reduced some of the above-mentioned positive effects of exercise training.
Exercise training, angiogenesis and resveratrol With advancing age and inactivity, muscle capillarization is decreased, which may contribute to decreased muscle function and physical capacity. In agreement with previous observations, the present work shows that exercise training induces a marked angiogenic response and increases capillarization in skeletal muscle in aged individuals. Muscle protein and interstitial levels of pro-angiogenic VEGF were increased as were the amount of VEGF receptor 2. Although resveratrol in theory targets the same signaling molecules as exercise, resveratrol supplementation appeared to limit, rather than improve, angiogenesis in sedentary subjects and, more pronounced, the angiogenic response to exercise training.
Vascular function in essential hypertension Increased vascular resistance is a hallmark of essential hypertension and, measurements on the forearm have demonstrated impaired vascular function in individuals with essential hypertension compared to normotensive individuals. In this thesis, vascular function was determined in the leg, as much less data on vascular function exist on locomotor muscle. Contrary to the previous findings on forearm, vascular responsiveness to arterially infused vasodilators acetylcholine and adenosine was not different between normotensive and hypertensive subjects. Nevertheless, active hyperemia in the leg was reduced in the hypertensive compared to the normotensive subjects, indicating a modest impairment in vascular function in the hypertensive subjects. Moreover, although pharmacological inhibition of nitric oxide and prostacyclin formation during exercise affected exercise hyperemia similarly in normotensive and hypertensive subjects, circulating nitric oxide metabolites and the capacity to form interstitial prostacyclin was lower in hypertensive subjects.
Adaptive response to exercise training on vascular function in individuals with essential hypertension In accordance with many previous studies, we found that a period of exercise training led to a reduction in arterial blood pressure in hypertensive subjects. A training-induced lowering of blood pressure can be explained by several mechanisms of which one is an improved vasodilator/vasoconstrictor balance. Our results show that the capacity to form nitric oxide and prostacyclin was increased in hypertensive subjects and the responsiveness to arterially infused acetylcholine was increased. Moreover, inhibition of nitric oxide and prostacyclin restored blood pressure during exercise to pre-training values. Combined, these observations strongly suggest that nitric oxide and prostaglandin are important in the blood pressure reducing effect of exercise training.
Capillarization and ultrastructure in essential hypertension Structural alterations in various parts of the vascular network, such as thicker and less compliant arterial walls, have been related to essential hypertension. Here we provide evidence for that essential hypertension is associated with structural adaptations also at the capillary level, as evident by decreased capillary lumen area and a tendency for increased basement membrane thickness in the skeletal muscle. The physiological consequences of these alterations are unknown but may constitute a limitation for diffusion of oxygen and nutrients. Increased basement membrane thickness has also been associated with more severe vascular diseases, which hypertension may lead to. Another novel observation in this thesis was that exercise training decreased capillary basement membrane thickness and increased capillary lumen area in the hypertensive subjects. In addition, as expected, exercise training led to angiogenesis as evident by an increased protein expression of a number of angiogenic factors and increased capillarization in both normotensive and hypertensive subjects.
Physical activity, resveratrol and endogenous antioxidants In aged individuals, the presence of ROS may be excessive, due to increased ROS formation and reduced antioxidant defense capacity. Such an increase in oxidative stress could lead to cell damage and inflammation. The present work shows that a period of exercise training in aged men can lower markers of basal oxidative stress and inflammation in skeletal muscle. The effect of training on markers of oxidative stress was likely, at least in part, due to a increase in skeletal muscle levels of SOD2, as the potential for ROS formation actually increased as evidenced by an increase in the expression of NAD(P)H oxidase. This latter finding of a training induced increase in NAD(P)H oxidase emphasizes the importance of ROS for muscle function and adaptation and to some extent even questions the theory of harmful oxidative stress in healthy aged individuals. Our studies were not able to support a positive effect of resveratrol supplementation on markers of oxidative stress or inflammation in aged individuals. In contrast, resveratrol supplementation actually reduced some of the above-mentioned positive effects of exercise training.
Exercise training, angiogenesis and resveratrol With advancing age and inactivity, muscle capillarization is decreased, which may contribute to decreased muscle function and physical capacity. In agreement with previous observations, the present work shows that exercise training induces a marked angiogenic response and increases capillarization in skeletal muscle in aged individuals. Muscle protein and interstitial levels of pro-angiogenic VEGF were increased as were the amount of VEGF receptor 2. Although resveratrol in theory targets the same signaling molecules as exercise, resveratrol supplementation appeared to limit, rather than improve, angiogenesis in sedentary subjects and, more pronounced, the angiogenic response to exercise training.
Vascular function in essential hypertension Increased vascular resistance is a hallmark of essential hypertension and, measurements on the forearm have demonstrated impaired vascular function in individuals with essential hypertension compared to normotensive individuals. In this thesis, vascular function was determined in the leg, as much less data on vascular function exist on locomotor muscle. Contrary to the previous findings on forearm, vascular responsiveness to arterially infused vasodilators acetylcholine and adenosine was not different between normotensive and hypertensive subjects. Nevertheless, active hyperemia in the leg was reduced in the hypertensive compared to the normotensive subjects, indicating a modest impairment in vascular function in the hypertensive subjects. Moreover, although pharmacological inhibition of nitric oxide and prostacyclin formation during exercise affected exercise hyperemia similarly in normotensive and hypertensive subjects, circulating nitric oxide metabolites and the capacity to form interstitial prostacyclin was lower in hypertensive subjects.
Adaptive response to exercise training on vascular function in individuals with essential hypertension In accordance with many previous studies, we found that a period of exercise training led to a reduction in arterial blood pressure in hypertensive subjects. A training-induced lowering of blood pressure can be explained by several mechanisms of which one is an improved vasodilator/vasoconstrictor balance. Our results show that the capacity to form nitric oxide and prostacyclin was increased in hypertensive subjects and the responsiveness to arterially infused acetylcholine was increased. Moreover, inhibition of nitric oxide and prostacyclin restored blood pressure during exercise to pre-training values. Combined, these observations strongly suggest that nitric oxide and prostaglandin are important in the blood pressure reducing effect of exercise training.
Capillarization and ultrastructure in essential hypertension Structural alterations in various parts of the vascular network, such as thicker and less compliant arterial walls, have been related to essential hypertension. Here we provide evidence for that essential hypertension is associated with structural adaptations also at the capillary level, as evident by decreased capillary lumen area and a tendency for increased basement membrane thickness in the skeletal muscle. The physiological consequences of these alterations are unknown but may constitute a limitation for diffusion of oxygen and nutrients. Increased basement membrane thickness has also been associated with more severe vascular diseases, which hypertension may lead to. Another novel observation in this thesis was that exercise training decreased capillary basement membrane thickness and increased capillary lumen area in the hypertensive subjects. In addition, as expected, exercise training led to angiogenesis as evident by an increased protein expression of a number of angiogenic factors and increased capillarization in both normotensive and hypertensive subjects.
| Original language | English |
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| Place of Publication | Copenhagen |
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| Publisher | Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen |
| Publication status | Published - 2014 |