Physical activity and the stress of shear: Vasoprotective or vasopreventative?

Regular physical activity lowers the risk profile for atherosclerosis and is associated with a 50% reduction in adverse events from coronary artery disease (Morris, Heady, Raffle, Roberts, & Parks, 1953), with elite athletes living longer than the general population (Garatachea et al., 2014). Thus, exercise confers substantial cardiovascular risk reduction, and this may be explained, in part, by enhanced vascular endothelial function. The endothelium is a single-cell layer that lines the luminal surface of arteries and is constantly subjected to haemodynamic forces. Our understanding of how the arterial endothelium recognizes and transduces these stimuli is rapidly evolving, and it is likely to involve many intracellular signalling cascades that are transmitted through the cytoskeleton to the intimal region at the basal endothelial surface. Complex interactions between integrins, actin filaments, caveolae, the glycocalyx, primary cilia, adherence/gap junction proteins, ion channels, G protein-coupled receptors and receptor tyrosine kinases ultimately determine endothelial cell function, phenotype, fate and gene expression. During acute exercise, the endothelium is subjected to hyperaemia-associated increases in shear stress, the frictional force exerted against the endothelium. Acute increases in shear stress rapidly stimulate the synthesis of vasodilators [i.e. nitric oxide (NO) and endothelium-derived hyperpolarizing factors] and can be used to examine endothelial function [flow-mediated dilatation (FMD)]. Repeated bouts of increased shear stress (i.e. exercise training) induce a vasoprotective endothelial cell phenotype, improve FMD and prevent age-associated declines in endothelial function. Despite the beneficial effects of exercise training on endothelial function, young athletes do not necessarily exhibit enhanced FMD relative to age-matched physically inactive control subjects. Instead, endothelial adaptation may become apparent only in the acute setting, when the vasculature is challenged. For instance, young athletes may exhibit vasoprotection against vascular insults owing to enhanced antioxidant and anti-inflammatory defense (Das et al., 2018). Atherogenic shear stress patterns, characterized by oscillatory shear stress (i.e. heightened retrograde shear stress, yielding a low time-averaged mean), reduce FMD in young, healthy adults, but this can be prevented with ascorbate prophylaxis (Johnson, Mather, Newcomer, Mickleborough, & Wallace, 2013). Therefore, young athletes may be protected against atherogenic shear stress-induced endothelial dysfunction owing to improved redox homeostasis and attenuation of a free radical-mediated reduction in vascular NO bioavailability (i.e. reduced oxidative–nitrosative stress). This is of crucial importance, because atherosclerotic lesions occur preferentially at arterial segments that are chronically exposed to low mean and oscillatory shear stress; thus, protection against such a stressor might confer resilience against atherosclerosis in the long term. In this issue of Experimental Physiology, Garten, Darling et al. (2019) examined whether trained rowers (vascular adaptive benefits both systemic and localized) were potentially less susceptible to atherogenic shear stress-induced reductions in FMD. Male varsity rowers were tested 6 weeks into their training season and compared with untrained male control subjects. Reactive hyperaemia-induced FMD was examined in the brachial artery before and after 30 min of oscillatory shear stress ‘priming’ in the same artery, achieved by inflating a forearm cuff to 60 mmHg before the FMD. As previously observed amongst young athletes, baseline FMD was not elevated in the rowers despite markedly superior cardiorespiratory fitness. After the imposed oscillatory shear stress, both the athlete group and the control group experienced an equivalent reduction in FMD. However, this was accompanied by blunted reactive hyperaemia (surrogate measure of microvascular function) and shear rate stimulus, such that adjusting for the reduced stimulus abolished the reduction in FMD. The conclusion based on these findings was that oscillatory shear stress induced microvascular, but not conduit artery endothelial, dysfunction, and athletes appear equally vulnerable to atherogenic shear stress. Whether conduit artery endothelial function is preserved in athletes after atherogenic shear stress remains inconclusive and highlights the unavoidable limitation underpinning the reactive hyperaemia FMD technique, where the stimulus is uncontrolled and ultimately contingent upon intact/preserved microvascular function. Assessing FMD in response to either a targeted shear stress stimulus (i.e. handgrip exercise with real-time velocity output) or across a spectrum of shear stress stimuli (i.e. progressive handgrip exercise) would facilitate a more direct examination of conduit artery endothelial function independent of (altered) microvascular function. Regardless, the observation that microvascular function was reduced after the cuff intervention sparks intrigue. Why should this occur? Perhaps it occurs via the same putative mechanisms responsible for prolonged sitting-induced reductions in microvascular function, which include downstream vasoconstriction owing to venous distension and atherogenic shear stress patterns that may be occurring distal to cuff placement. In support, Garten, Hogwood et al. (2019) previously documented similar reductions in microvascular function in the lower limb after prolonged sitting in trained and untrained young adults. Although vasoprotection at the level of the conduit artery cannot be ruled out, young athletes appear to be as susceptible as their untrained peers to reductions in microvascular function after exposure to atherogenic shear stress patterns; an interesting, albeit counterintuitive observation that warrants further investigation. If the mechanisms driving the reductions in microvascular and/or conduit artery endothelial function after imposed oscillatory shear stress and prolonged sitting are overlapping, what are the molecular pathways responsible and why were the athletes not protected? From a purely thermodynamic perspective, millimolar concentrations of ascorbate are required to outcompete the superoxide-mediated scavenging of NO, i.e. three orders of magnitude more than current endogenous levels offer! Thus, the antioxidant status of even trained athletes might have been no match for a potential atherogenic shear stress-induced increase in oxidative–nitrosative stress. Additionally, it is important to highlight that Garten, Darling et al. (2019) relied on indirect biomarkers of lipid peroxidation (malondialdehyde) formed distal to the proximal free radical reaction pathway, and corresponding extended half-life. To uncover the deleterious effects of atherogenic shear stress on human endothelial function in vivo, we need to focus our molecular efforts in a more concerted manner in future studies, given the caveats described. However, an important point to note is that the devil is in the (duration) detail. Although athletes might well appear equally vulnerable to acute atherogenic shear stress, they are less likely to experience it as frequently or for as long as the sedentary population. Atherogenic shear stress manifests during the course of prolonged sitting, periods of increased sympathetic nerve activity and either as a cause or as a consequence of disease (e.g. hypertension, obstructive sleep apnoea, chronic obstructive pulmonary disease). Furthermore, exercise ‘priming’ can provide a window of vasoprotection against sitting-induced vascular impairments (Morishima, Restaino, Walsh, Kanaley, & Padilla, 2017). Let us not give up on exercise; it is as much about (vaso)prevention as it is about protection, and the present findings will no doubt stimulate further research!

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