551
INVITED REVIEW Exercise and vascular function: how much is too much?1 Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by LAFAYETTE COLLEGE on 07/01/14 For personal use only.
Matthew J. Durand and David D. Gutterman
Abstract: Exercise is a powerful therapy for preventing the onset of and slowing the progression of cardiovascular disease. Increased shear stress during exercise improves vascular homeostasis by both decreasing reactive oxygen species and increasing nitric oxide bioavailability in the endothelium. While these observations are well accepted as they apply to individuals at risk for cardiovascular disease, less is known about how exercise, especially intense exercise, affects vascular function in healthy individuals. This review highlights examples of how vascular function can paradoxically be impaired in otherwise healthy individuals by extreme levels of exercise, with a focus on the causative role that reactive oxygen species play in this impairment. Key words: exercise, reactive oxygen species, vasodilation, nitric oxide, flow mediated dilation. Résumé : L'exercice constitue une puissante thérapie pour prévenir la survenue et ralentir la progression de la maladie cardiovasculaire. La force de cisaillement accrue durant l'exercice améliore l'homéostasie vasculaire, tant en diminuant les espèces réactives d'oxygène qu'en augmentant la biodisponibilité de l'oxyde nitrique dans l'endothélium. Alors que ces observations sont bien acceptées quand elles s'appliquent a` des individus a` risque de développer une maladie cardiovasculaire, la mesure dans laquelle l'exercice, notamment l'exercice intense, affecte la fonction vasculaire des individus en santé est moins connue. Cet article de revue met l'accent sur des exemples où la fonction vasculaire peut, de manière paradoxale, être affectée négativement par des niveaux extrêmes d'exercice chez des individus par ailleurs en bonne santé, en se concentrant sur le rôle causal des espèces réactives d'oxygène dans cette détérioration. [Traduit par la Rédaction] Mots-clés : exercice, espèces réactives d'oxygène, vasodilatation, oxyde nitrique, dilatation dépendante du flux sanguin.
Introduction A delicate balance between reactive oxygen species (ROS) and nitric oxide (NO) exists within the vasculature. If the regional, subcellular concentrations of ROS increase beyond homeostatic levels in endothelial cells, vascular NO signaling can become corrupted, resulting in endothelial dysfunction that is manifested by vascular inflammation and proliferation (Forstermann 2010). Over time, this can lead to atherosclerosis and ultimately to cardiovascular events and increased mortality. A cornucopia of approaches has been proposed to mitigate the onset of endothelial dysfunction; however, routine physical exercise is universally considered one of the most powerful preventive and therapeutic interventions for cardiovascular disease (Naci and Ioannidis 2013). The beneficial effects of regular exercise are multifaceted, and prominently include an improvement in vascular function, which in part derives from a reduction in cellular ROS and restoration of NO bioavailability (Fig. 1). While the shift in the ROS–NO balance to favor NO improves vascular function and cardiovascular outcomes, recent evidence suggests that a “tipping point” may exist, whereby too much exercise becomes detrimental to the cardiovascular system (Nikolaidis et al. 2012). As with many physiological stimuli or lifestyle choices, a threshold may exist beyond which there are diminishing returns, or frankly, adverse effects. Indeed a U-shaped curve has been suggested with regard to exercise, where either extreme levels of activity or pronounced sedentary activity can be unhealthy, disrupting the NO–ROS balance similar to what is seen in cardiovascular disease. While this “exercise hormesis” theory has been described previously (Radak et al.
2005, 2008; La Gerche and Prior 2007; Ji et al. 2010) (Fig. 2), the unique focus of this review will be on vascular-specific adaptations to extreme resistance and endurance training, highlighting the detrimental role of increased ROS in the maladaptive processes observed at the extremes (both high and low) of exercise behavior.
The sedentary lifestyle and cardiovascular health Individuals who engage in regular exercise and physical activity have significantly lower rates of disability and an average life expectancy approximately 7 years longer than their sedentary counterparts (Sarna et al. 1993; Chakravarty et al. 2008). While no exact definition exists for what constitutes a “sedentary lifestyle”, it is generally agreed that activities which have a metabolic expenditure of
INVITED REVIEW Exercise and vascular function: how much is too much?1 Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by LAFAYETTE COLLEGE on 07/01/14 For personal use only.
Matthew J. Durand and David D. Gutterman
Abstract: Exercise is a powerful therapy for preventing the onset of and slowing the progression of cardiovascular disease. Increased shear stress during exercise improves vascular homeostasis by both decreasing reactive oxygen species and increasing nitric oxide bioavailability in the endothelium. While these observations are well accepted as they apply to individuals at risk for cardiovascular disease, less is known about how exercise, especially intense exercise, affects vascular function in healthy individuals. This review highlights examples of how vascular function can paradoxically be impaired in otherwise healthy individuals by extreme levels of exercise, with a focus on the causative role that reactive oxygen species play in this impairment. Key words: exercise, reactive oxygen species, vasodilation, nitric oxide, flow mediated dilation. Résumé : L'exercice constitue une puissante thérapie pour prévenir la survenue et ralentir la progression de la maladie cardiovasculaire. La force de cisaillement accrue durant l'exercice améliore l'homéostasie vasculaire, tant en diminuant les espèces réactives d'oxygène qu'en augmentant la biodisponibilité de l'oxyde nitrique dans l'endothélium. Alors que ces observations sont bien acceptées quand elles s'appliquent a` des individus a` risque de développer une maladie cardiovasculaire, la mesure dans laquelle l'exercice, notamment l'exercice intense, affecte la fonction vasculaire des individus en santé est moins connue. Cet article de revue met l'accent sur des exemples où la fonction vasculaire peut, de manière paradoxale, être affectée négativement par des niveaux extrêmes d'exercice chez des individus par ailleurs en bonne santé, en se concentrant sur le rôle causal des espèces réactives d'oxygène dans cette détérioration. [Traduit par la Rédaction] Mots-clés : exercice, espèces réactives d'oxygène, vasodilatation, oxyde nitrique, dilatation dépendante du flux sanguin.
Introduction A delicate balance between reactive oxygen species (ROS) and nitric oxide (NO) exists within the vasculature. If the regional, subcellular concentrations of ROS increase beyond homeostatic levels in endothelial cells, vascular NO signaling can become corrupted, resulting in endothelial dysfunction that is manifested by vascular inflammation and proliferation (Forstermann 2010). Over time, this can lead to atherosclerosis and ultimately to cardiovascular events and increased mortality. A cornucopia of approaches has been proposed to mitigate the onset of endothelial dysfunction; however, routine physical exercise is universally considered one of the most powerful preventive and therapeutic interventions for cardiovascular disease (Naci and Ioannidis 2013). The beneficial effects of regular exercise are multifaceted, and prominently include an improvement in vascular function, which in part derives from a reduction in cellular ROS and restoration of NO bioavailability (Fig. 1). While the shift in the ROS–NO balance to favor NO improves vascular function and cardiovascular outcomes, recent evidence suggests that a “tipping point” may exist, whereby too much exercise becomes detrimental to the cardiovascular system (Nikolaidis et al. 2012). As with many physiological stimuli or lifestyle choices, a threshold may exist beyond which there are diminishing returns, or frankly, adverse effects. Indeed a U-shaped curve has been suggested with regard to exercise, where either extreme levels of activity or pronounced sedentary activity can be unhealthy, disrupting the NO–ROS balance similar to what is seen in cardiovascular disease. While this “exercise hormesis” theory has been described previously (Radak et al.
2005, 2008; La Gerche and Prior 2007; Ji et al. 2010) (Fig. 2), the unique focus of this review will be on vascular-specific adaptations to extreme resistance and endurance training, highlighting the detrimental role of increased ROS in the maladaptive processes observed at the extremes (both high and low) of exercise behavior.
The sedentary lifestyle and cardiovascular health Individuals who engage in regular exercise and physical activity have significantly lower rates of disability and an average life expectancy approximately 7 years longer than their sedentary counterparts (Sarna et al. 1993; Chakravarty et al. 2008). While no exact definition exists for what constitutes a “sedentary lifestyle”, it is generally agreed that activities which have a metabolic expenditure of
