Abstract
Vascular endothelial function is essential for maintenance of health of the vessel wall and for vasomotor control in both conduit and resistance vessels. These functions are due to the production of numerous autacoids, of which nitric oxide (NO) has been the most widely studied. Exercise training has been shown, in many animal and human studies, to augment endothelial, NO-dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential for autacoid bioavailability. Recent human studies also indicate that exercise training may improve endothelial function by up-regulating eNOS protein expression and phosphorylation. While improvement in NO vasodilator function has been less frequently found in healthy subjects, a higher level of training may lead to improvement. Regarding time course, studies indicate that short-term training increases NO bioactivity, which acts to homeostatically regulate the shear stress associated with exercise. Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodelling and structural normalization of shear. Given the strong prognostic links between vascular structure, function and cardiovascular events, the implications of these findings are obvious, yet many unanswered questions remain, not only concerning the mechanisms responsible for NO bioactivity, the nature of the cellular effect and relevance of other autacoids, but also such practical questions as the optimal intensity, modality and volume of exercise training required in different populations.
Introduction
The endothelium produces numerous paracrine substances, including nitric oxide (NO), which help maintain the health of the vascular wall and regulate vasomotor function. Nitric oxide (NO) is a labile, lipid soluble gas synthesized in endothelial cells from the amino-acid l-arginine through the action of endothelial nitric oxide synthase (eNOS) (Palmer et al. 1988). It is released both basally and in response to pharmacological stimulation (Vallance et al. 1989). The likely physiological stimulus to endothelial NO production has been identified as increased flow through the vessel lumen (Pohl et al. 1986; Rubanyi et al. 1986), with acute NO-mediated vaso-dilatation tending to normalize shear stress (Hutcheson & Griffith, 1991; Koller & Kaley, 1991; Neibauer & Cooke, 1996; Dimmeler & Zeiher, 2003). These findings raised the possibility that NO may contribute to exercise hyperaemia, as exercise is associated with increased pulse pressure and pulsatility, and that repeated exposure to increased shear stress, as a result of exercise training, may improve the bioavailability of NO.
Exercise training is associated with reduction in primary (Hakin et al. 1999; Sesso et al. 2000; Myers et al. 2002) and secondary vascular events (Jolliffe et al. 2001), but the effect of exercise on conventional risk factors (Blair et al. 1984; Tran & Weltman, 1985; Holloszy et al. 1986; Blair, 1993; Williams, 1996; Malfattoo et al. 1998; Kelley, 1999; Smith et al. 1999; El-Sayed et al. 2000) cannot solely account for the magnitude of risk reduction, since the association with reduced mortality is independent of these risk factors (Dimmeler & Zeiher, 2003). Moreover, improvements in conduit and resistance vessel endothelial function can occur independent of changes in cardiovascular risk factors (Green et al. 2003). Direct shear-stress-mediated effects on the vascular endothelium may therefore provide a plausible explanation for the reduction in coronary events associated with exercise training. The purpose of this review is to summarize the extant and evolving evidence from human studies regarding the contribution of endothelium-derived NO to exercise hyperaemia and the impact of exercise training on NO vasodilator function.
Summary and conclusions
In an excellent recent review for this journal, Booth et al. (2002) suggested that humans possess a genome which was selected during an era of obligatory physical activity, whereas contemporary Western lifestyle is characteristically sedentary. In this context, habitual exercise restores perturbed homeostatic mechanisms towards the normal physiological range. Analysis of the studies presented in this review reveal data consistent with this hypothesis. The majority of those studies undertaken in subjects with a priori impaired NO-related vasodilator function produced improvement in conduit or resistance vessel function, whereas studies in healthy normal subjects have been less consistent. That is, depressed endothelial function is more amenable to improvement by exercise training than is ‘normal’ endothelial function in the young and healthy, who might need a higher intensity or volume of exercise training for benefit to be apparent. This raises the intriguing possibility of a threshold effect for training on endothelial function which may be determined by age, fitness or pathological state. Studies are now beginning to emerge regarding the optimal modality and intensity of exercise for improvement in vascular structure and function and intriguing relationships between these factors, endo-thelial function and oxidative stress are becoming apparent.
Endothelial function may improve after as few as 7 days in trained animals (Wang et al. 1993; McAllister & Laughlin, 1997). In healthy humans, 4 weeks of training improved basal NO-related end-othelial function in healthy subjects (Kingwell et al. 1997b). However, studies that have identified improved stimulated endothelium-dependent vasodilatation have prescribed at least 10 weeks of training in normal subjects (Clarkson et al. 1999; DeSouza et al. 2000). Pathological states associated with depressed NO bioactivity may respond more rapidly to training, with endothelial function improving after as little as 4 weeks (Hornig et al. 1996; Hambrecht et al. 2000c), but returning rapidly to baseline following the cessation of training (Hornig et al. 1996; Maiorana et al. 2000, 2001a). Conditions in which exercise training can improve NO-dependent endothelial vasodilator function include CAD, type 2 diabetes, obesity, hypercholesterolaemia, hypertension and CHF. In the latter, peripheral abnormalities typically limit V˙O peak and improvement in vasodilator function correlates with changes in functional capacity and may improve cardiac function by decreasing afterload. Few studies have investigated the relationship between improvements in vasodilator function and functional capacity in other conditions.
It is likely that exercise training improves NO vasodilator function by both direct and indirect means. Conventional risk factors impair NO-mediated endothelial function and beneficial training effects on risk factor profiles are widely accepted, although the evidence is less convincing in the secondary prevention setting in which pharmacotherapy has a greater impact. Nonetheless, exercise training consistently improves NO function in patients with cardiovascular risk factors and disease, including those on optimal medical regimes and in the absence of risk factor modulation. These findings strongly implicate a direct effect of exercise on the vasculature, mediated through intermittent increases in endothelial shear stress. This effect may, in turn, be mediated through up-regulation of eNOS or decreased free radical degradation of NO, with evidence beginning to emerge for both possibilities (Fukai et al. 2000; Dimmeler & Zeiher, 2003; Hambrecht et al. 2003). The possibility that synergistic benefits accrue from combined pharmacological and exercise-mediated shear stress strategies remains to be investigated in humans.
Vascular remodelling with increase in vessel diameter occurs with prolonged exercise (Leon & Bloor, 1968; Kramsch et al. 1981; Miyachi et al. 2001; Prior et al. 2003). This process teleologically constitutes a longer term mechanism for reducing shear stress on a more sustained basis, allowing NO bioactivity to return towards pre-training levels. This hypothetical schema, which promotes shear stress as a homeostatically regulated variable, explains the observation that improvement in NO-related vasodilatation is observed in short to medium term studies, whereas longer term training studies, associated with arterial remodelling, have not usually reported improved endothelial function. Whilst the mechanisms responsible for mediating vascular structural change remain largely undefined, there is strong evidence that NO plays an important role in arterial remodelling (Kamiya & Togawa, 1980; Langille & O’Donnell, 1986; Zarins et al. 1987; Gibbons & Dzau, 1994; Tronc et al. 1996; Rudic et al. 1998; Prior et al. 2003). These findings reinforce the conclusion that future questions regarding the physiological effects of exercise training on the endothelium will be best resolved if studies consider the direct effects of various interventions on the vessel wall.