Ageing, exercise training, and resistance vessels: more than just no NO?

It is well established that the healthy endothelium plays an important role in modulating vascular tone via the tonic and stimulated release of numerous vasoactive substances, as well as in providing protection from the development of thrombosis and atherosclerotic vascular disease (Rubanyi, 1993). Accumulating evidence indicates that there is a significant impairment in endothelial function with age even in healthy adults (Taddei et al. 2000), which most likely contributes to their increased risk for cardiovascular disease. Additionally, impaired vasodilator responses to endothelium-dependent stimuli (e.g. acetylcholine infusions, flow-mediated vasodilatation) have led investigators to propose that endothelial dysfunction might explain the reduced muscle blood flow responses during dynamic exercise in older adults (Lawrenson et al. 2003), and therefore contribute to exercise intolerance with age. Interestingly, recent findings indicate that regular aerobic exercise can prevent or improve endothelial function in older healthy individuals (Taddei et al. 2000). Therefore, given the respective influences of ageing (negative) and regular exercise (positive) on endothelial function and cardiovascular health, it is of obvious importance to elucidate and understand the mechanisms involved in this regulation of vascular function. In this issue of The Journal of Physiology, Muller-Delp and colleagues (Spier et al. 2004) provide insight into the mechanisms by which ageing impairs and regular exercise preserves endothelial function in first order (1A) arterioles of rats in muscles differing in fibre composition (soleus –highly oxidative; gastrocnemius – low oxidative). Consistent with previous work from this group (Muller-Delp et al. 2002), ageing selectively reduced acetylcholine-mediated vasodilatation in arterioles dissected from the soleus muscle (not gastrocnemius), and these responses were no longer different after acute inhibition of nitric oxide synthase (NOS). Interestingly, arteriolar expression of eNOS mRNA was unaltered with age (and eNOS protein content elevated), indicating that a reduction in enzyme expression is not the mechanism by which NO bioavailability is reduced in the skeletal muscle microcirculation of older rats. With respect to exercise training, young trained rats demonstrated the greatest vasodilator responses to acetylcholine, and regular physical activity in a group of older rats preserved these dilator responses. NOS inhibition abolished all training-related differences in endothelium-dependent vasodilatation, indicating that the greater responses in the trained groups were mediated via NO. Additionally, the greater vasodilator responses to acetylcholine in both young and older trained groups (compared with their sedentary counterparts) were associated with elevated arteriolar eNOS mRNA expression and eNOS protein content. Finally, similar to age-related changes in vasodilator responses, exercise training did not significantly influence acetylcholine-mediated vasodilatation of arterioles from the gastrocnemius muscle. Several findings from the present investigation deserve comment. First, the observation of impaired acetylcholine-mediated vasodilatation in older rats without any reduction in arteriolar eNOS expression is consistent with the idea that ageing is associated with an increased production of vascular superoxide anion and other reactive oxygen species (i.e. oxidative stress). That is, the ability of aged vessels to produce and release NO is relatively intact, but reactive oxygen species readily inactivate NO and subsequently impair NO-mediated vasodilatation. Indeed, recent studies in humans have demonstrated that acute infusion of the antioxidant ascorbic acid can markedly improve endothelial vasodilator function in older healthy adults (Taddei et al. 2000). Second, the authors report a significant elevation in eNOS enzyme expression in the arterioles of trained animals, in agreement with previous findings. However, eNOS expression was similarly elevated in the young and older rats, indicating that the ability of regular exercise to induce an increase in eNOS enzyme expression in the skeletal muscle microcirculation is preserved with age. Finally, the specificity of the effects of ageing and exercise training on endothelial function of arterioles from the soleus versus gastrocnemius muscles is certainly intriguing. Despite years of investigation focused on understanding the interactions between ageing, regular physical activity and endothelial function, several questions still remain. First, do age-related impairments and exercise-related improvements in endothelial vasodilator function in the trained limbs of older adults (or animals) result in corresponding impairments or improvements in skeletal muscle blood flow responses and/or distribution during exercise? To date, there has been much speculation on this topic without any studies truly designed to test this hypothesis. Second, what are the mechanisms governing the changes in endothelial function of arterioles in slow versus fast-twitch muscles? Flow-mediated vasodilatation is impaired with age in arterioles from fast-twitch muscles (Muller-Delp et al. 2002), so perhaps some of the present findings related to ageing and exercise training are stimulus specific (i.e. pharmacological versus physiological). Further, considering that human skeletal muscle is typically ‘mixed’ and contains a mosaic of slow- and fast-twitch fibres, can these findings be translated to humans, and if so, what are the functional and clinical implications for ageing humans and other populations demonstrating loss of muscle mass and/or changes in muscle fibre composition? Finally, the interactions between ageing, exercise training and oxidative stress in the rat microcirculation deserve investigation to aid in our understanding of the regulation of endothelial function from molecule to humans. The recent findings of Spier et al. (2004) provide more scientific evidence for the ability of regular exercise training to improve endothelial vasodilator function in ageing animals, and further promote its efficacy as a means to improve vascular health. However, divergent effects of ageing and exercise training on arterioles from different muscle fibres remind us of the complex regulation of vascular function and deserves further study.