Effect of exercise training on endothelium‐derived nitric oxide function in humans

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.

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

“…An increase in shear stress (eg, during physical activity) has been proved to enhance eNOS mRNA and protein expression and promote phosphorylation of the serine 1177 residue of the enzyme, thereby boosting vascular NO production 31, 32, 33, 34. However, animal studies suggest that after a few months of exercise training, eNOS expression levels reduce to the preexercise state 35. This decline is explained by the fact that the normalization of shear stress at an early adaptive state requires a decline in vascular tone and, hence, vasodilatation; however, this change does not occur at a later stage when the vessels have already grown 1…”

Cerebral blood flow and cerebrovascular reactivity at rest and during sub-maximal exercise: Effect of age and 12-week exercise training

“…Cerebrovascular vasodilatation in response to hypercapnia is, in part, dependent upon NO bioavailability (Peebles et al 2007). Nitric oxide has been reported to increase with exercise training (Green et al 2004;Kingwell et al 1997). Exercise training has also been shown to increase systemic endothelium-dependent vasodilatation (a NO-mediated response) (Green et al 2004;Clarkson et al 1999;Tinken et al 2008).…”

“…One cross-sectional study indicated that higher fitness is related to larger frontal and temporal volumes of grey matter (Colcombe et al 2006). Other potential mechanisms may involve more endotheliumdependent vasodilatation as a result of more NO bioavailability (Green et al 2004) and/or cerebral angiogenesis (Rhyu et al 2010;Swain et al 2003;Ding et al 2006;Black et al 1990). In support of this, ageinduced cerebral atrophy appears to be less marked in those with higher aerobic fitness (Colcombe et al 2003).…”

Time-course of vascular adaptations during 8 weeks of exercise training in subjects with type 2 diabetes and middle-aged controls

“…Previous studies suggest that improvement in vascular function after dynamic exercise training is not universal (Green et al 2004;Green et al 2011), especially in healthy volunteers. The presence of time-dependent adaptations in vascular function in response to exercise training may partly explain this observation.…”

“…The presence of time-dependent adaptations in vascular function in response to exercise training may partly explain this observation. Originally based on findings in animals (Laughlin 1995), human studies have also demonstrated that short-term exercise training enhances conduit artery function in subjects with cardiovascular risk factors or disease (Green et al 2004;Maiorana et al 2001;Watts et al 2004), whilst prolonged training induces structural changes (i.e. increased diameter) (Brown 2003;Prior et al 2003).…”