Old cells die hard – sympatholysis and the ageing erythrocyte

Skeletal muscle blood flow is tightly regulated by multiple redundant pathways integrating local vasoconstrictor and vasodilator signals to support optimal function. Insufficiencies in signalling cascades may lead to mismatching of local perfusion and tissue metabolic demand, compromising skeletal muscle's capacity to perform work. Healthy ageing has been associated with decrements in peripheral vascular function, a subsequent mismanagement of blood flow and reductions in exercise capacity. As exercise capacity is both a predictor of all-cause mortality and a major factor in overall quality of life, elucidating the underpinnings of this dysfunction is vital for the development of new treatments and therapeutic options to combat the decline of vascular function with age. Recently, Hearon and colleagues have conducted a series of studies on the interaction of dilatory and constrictor pathways in regulating muscle blood flow. The latest study in this series, published in this issue of The Journal of Physiology, examined the capacity of the endothelium to modulate adrenergic vasoconstriction in ageing adults (Hearon et al. 2020). The ability of vasculature within exercising skeletal muscle to locally inhibit sympathetic neural vasoconstriction during exercise is known as ‘functional sympatholysis’. Although vasodilatation and sympatholysis exhibit numerous mechanistic similarities such as key chemical mediators and downstream signalling cascades, these processes are each distinct phenomena and the efficacy of one may not be predictive of the other. The health and function of the endothelium has come under scrutiny as a key site of integration and coordination of vascular tone, and for its role in age-associated decrements in peripheral vascular function. While older adults exhibit impaired sympatholysis during exercise, they maintain the ability to blunt sympathetically mediated vasoconstriction during exogenous ATP administration (Kirby et al. 2011). These findings suggest that these sympatholytic pathways are intact in older adults, with age-associated decrements in sympatholysis attributable rather to a reduction in endothelial signalling. Therefore, the authors aimed to test the hypothesis that endothelium-mediated sympatholytic pathways are preserved in healthy ageing. The authors employ an effective and replicable methodology to assess sympatholysis, following a formulaic protocol measuring vascular conductance at rest, during a hyperaemic condition (i.e. exercise and/or vasodilator infusion), and during infusion of a sympathomimetic vasoconstrictor agent. The efficacy of sympatholysis is determined by the magnitude of vasoconstriction with sympathomimetic administration, with a reduced vasoconstrictor response indicative of improved sympatholysis. Notable adjustments in the protocol of this study allow for novel, informative interpretations between the responses of younger and ageing adults. The experimental protocol employed by Hearon et al. (2020) in older adults closely mirrors that of their prior work in young adults (Hearon et al. 2016), using these previous data as a comparison group. Brachial artery blood flow was measured, and forearm vascular conductance (FVC) was determined by normalizing for mean arterial pressure, with local arterial phenylephrine (an α1-adrenergic agonist) infusion to assess sympatholysis. Phenylephrine produces adrenergic vasoconstriction independently of prejunctional negative feedback by α2-adrenoreceptors. Additionally, in this forearm model sympatholysis of α1-adrenergic vasoconstriction is more susceptible to age-related impairments than α2-adrenergic vasoconstriction, and may be of greater clinical relevance. As sympatholysis is a measure of the ability of the vasculature to blunt the net vasoconstrictor signal transduced under control conditions, age-associated impairments in α1-constrictor signal transduction may muddle comparisons between younger adults. To account for this, phenylephrine infusion rates in older adults were doubled to achieve a comparable transduced vasoconstrictor signal to that of younger adults under control conditions. The experimental protocol consisted of 5 trials, each designed to assess the efficacy of sympatholysis during different conditions of hyperaemia and endothelial stimulation. The protocol was conducted two times, once for each of the endothelium-mediated vasodilators acetylcholine and ATP. The hyperaemic trial conditions consisted of (1) control vasodilator infusion to produce a chemical and shear stimulus known to be non-sympatholytic, (2) mild intensity (5% of maximal voluntary contraction; MVC) rhythmic handgrip exercise (HG) to elicit a mild but non-sympatholytic exercise stimulus, (3) moderate intensity (15% MVC) HG known to evoke a potent sympatholytic effect in young adults, (4) mild intensity HG with combined vasodilator infusion previously observed to augment sympatholysis in young adults (Hearon et al. 2016), and (5) moderate intensity HG with combined vasodilator infusion to match the hyperaemic response of young adults. Importantly, vasodilator dosages were titrated to match FVC between trials to compare similar hyperaemic stimuli. Controlling the FVC response between trials standardizes shear stress, and provides a nuanced assessment of the relative effects of stimulating specific endothelial pathways on sympatholysis. Specifically, in trials 1 and 4 dilators were titrated to match FVC responses observed during moderate intensity HG in older adults. In trial 5, FVC was increased by 10–20% to compensate for the observed 10–20% decrease in FVC typically observed during moderate intensity exercise in older adults compared to younger adults. While exogenous vasodilator infusion cannot precisely emulate concentrations of specific vasodilators produced endogenously in young adults at a matched exercise intensity, this provides a more physiologically relevant comparison to begin teasing out the weak link in the ageing sympatholytic pathway. In older adults, phenylephrine-mediated vasoconstriction was blunted only during combined moderate (but not light) intensity HG with vasodilator infusion in both acetylcholine and ATP protocols, indicating that the combined stimulus was sufficient to activate vascular sympatholytic mechanisms. This is in contrast to the responses observed previously in young adults where vasoconstriction was blunted during moderate HG alone, and even during mild HG with combined acetylcholine/ATP infusion. From these results, the authors conclude that endothelium-dependent sympatholytic pathways are preserved in healthy ageing and can be activated when provided a sufficient signal, and the impairments of sympatholysis characteristic of ageing are more likely to be attributable to a loss of endothelial signalling during exercise. The finding that sympatholytic pathways are preserved in healthy ageing provides valuable insight into its mechanistic underpinnings. The authors suggest that impaired sympatholysis in older adults may not be attributable to deficiencies within the vasculature itself, but rather in the source of the signal – specifically erythrocyte ATP release. High-dose ATP infusion (∼5.07 μg dL forearm volume−1 min−1; calculated from Kirby et al. 2011) abolishes sympathetic vasoconstriction, whereas the ∼75% lower dosage employed in the ATP control trial of the present study (∼1.282 μg dL forearm volume−1 min−1) had no effect on sympatholysis, alluding to a requisite signalling threshold to blunt sympathetic vasoconstriction. During trial 5 (moderate HG with vasodilator infusion), the dosage was even lower (∼0.58 μg dL forearm volume−1 min−1), less than half that of the ATP control trial. Despite the lower dose, the combined exercise and vasodilator stimulus was sufficient to blunt constriction where moderate exercise alone did not. Endogenous signalling during moderate HG in older adults falls short of sympatholytic threshold levels, with impaired erythrocyte ATP release a promising culprit. This interpretation is based on the assumption of a fully functional, merely under-stimulated sympatholytic pathway. Intravascular ATP binds to endothelial P2Y2 receptors, and while P2Y2 expression is modulated by training state, age-related decrements have been reported (Mortensen et al. 2012). Whether healthy ageing is directly responsible for this and the functional implications of reduced P2Y2 content remains to be elucidated, but the possibility of signalling cascade impairments downstream of erythrocyte ATP release merit future consideration. Identifying erythrocyte-mediated ATP release as a key player in age-associated impairments in sympatholysis invites further investigation into erythrocyte function with age. To this end, the authors suggest that declining erythrocyte deformability with age contributes to reduced ATP release. While reduced deformability appears to be characteristic of healthy ageing, changes in circulating sex hormones in young versus post-menopausal women may be critical to erythrocyte function. Grau et al. (2018) recently investigated the effects of fluctuating plasma oestrogen levels across the menstrual cycle on various haematological factors, including erythrocyte deformability. They present novel evidence that circulating oestrogen enhances erythrocyte deformability. To date, the effects of oestrogen on sympatholysis are somewhat equivocal, and while mounting evidence suggests oestrogen augments sympatholysis, the specific pathways are unclear. Enhanced erythrocyte deformability via oestrogen may be a novel mechanism of sex differences in sympatholysis, and moreover between young and post-menopausal women. With regard to the focus study, this mechanism may have contributed to the finding that sympatholysis was impaired in older adults when compared to the younger cohort of Hearon et al. (2016). Although oestrogen was not reported in these studies, even when testing during the early follicular phase, plasma oestrogen levels are higher on average in young women than post-menopausal women. Elevated circulating oestrogen in the young female participants may have improved erythrocyte deformability, thereby augmenting erythrocyte ATP release and sympatholysis. Adding to its repertoire of vasoactive properties, exploration of the effect of circulating oestrogen on sympatholysis remains an exciting prospect. The present study by Hearon et al. (2020) illustrates that the endothelium maintains the ability to blunt adrenergic vasoconstriction through healthy ageing, and emphasizes the erythrocyte as a likely culprit for reduced endothelial signalling with age. These observations shed light on the complex nature of impairments in vascular function with age, and set the stage for future therapeutic approaches targeting the erythrocyte. No competing interests declared Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.

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