Signalling of vasodilatation across an exercise transient

Historically, the mechanisms contributing to the local regulation of exercise blood flow (hyperaemia) and vasodilatation have been examined after a steady-state response has been achieved (e.g. a few minutes of constant rhythmic exercise). Prior investigations have demonstrated that no one independent vasoactive substance or mechanical component is solely responsible for the increase in vasodilatation during steady-state exercise. Rather, an intricate redundancy is present whereby when one signalling pathway is inhibited or reduced, skeletal muscle hyperaemia and vasodilatation are preserved, effectively ensuring adequate perfusion of skeletal muscle (Joyner & Casey, 2015). By the nature of these studies and measurements, regulation of hyperaemia and vasodilatation at the onset of exercise has received far less attention, despite regulatory responses evident as soon as after a single skeletal muscle contraction. Exercise hyperaemia is well matched to the metabolic demands of contracting tissue and regulated by resistance arteries and arterioles (Joyner & Casey, 2015). Rapid regulatory responses following single skeletal muscle contractions provide insight into vascular control mechanisms that initiate exercise hyperaemia/vasodilatation versus those that sustain hyperaemia/vasodilatation during steady-state exercise. In this context, emerging evidence from both human and animal models use single, brief skeletal muscle contractions and repetitive/twitch contractions to elucidate signalling events that are integral in the initiation of exercise hyperaemia. This response has been termed (contraction-induced) rapid onset vasodilatation (ROV), describing the rapid, robust vasodilatation hypothesized to be a mechanism implicated in the regulation of blood flow and vasodilatation during exercise. In a recent article published in The Journal of Physiology, Sinkler and Segal (Sinkler & Segal, 2017) examined mechanisms contributing to the rapid vasodilator response to single skeletal muscle (gluteus maximus) tetanic contractions, as well as to rhythmic twitch contractions within a microvascular resistance network (e.g. feed arteries, 1A, 2A, 3A arterioles) prior to and following endothelial cell damage, and pharmacological inhibition of vasodilator pathways. ROV responses were examined using brief (500 ms, 100 Hz) tetanic twitches evoking rapid (<1 s) vasodilatation. Slow onset vasodilatation (SOV) was elicited using rhythmic twitch contractions (30 s, 4 Hz). SOV dynamics began 10–15 s after initiation of stimulation and plateaued within 30 s. Endothelial cell damage was elicited with light-dye treatment localized to the midway point between the feed artery and primary arteriole (1A). Following disruption of conducted vasodilatation along the endothelium, ROV responses to tetanic twitches were effectively eliminated in feed arteries, but still present in 1A arterioles, indicating that endothelial signalling was required for ROV to ascend to feed arteries. Endothelial cell damage did not have any effect on SOV in either feed arteries or 1A arterioles until exposed to a nitric oxide synthase inhibitor (NOS; l-NAME), which abolished vasodilator responses in feed arteries but not 1A arterioles. To examine how the endothelium is implicated in exercise vasodilatation, the muscle preparation was exposed to individual and combined inhibition of autacoids (cyclo-oxygenase (COX) and NO) and hyperpolarization via calcium-sensitive K+ channels (SKCa and IKCa via TRAM 34 and UCL 1684, respectively). Inhibition of endothelial hyperpolarization alone, and in combination with autacoids, attenuated peak ROV responses and doubled the time to reach peak diameter in proximal feed arteries and 1A, but not 2A and 3A arterioles. Conversely, inhibition of respective vasodilating pathways during rhythmic contractions did not attenuate SOV responses. These results suggest a number of conclusions: (1) the endothelium is critical to vasodilatation during exercise, particularly at the onset. This conclusion is evidenced by loss of ROV responses in feed arteries when the endothelium was damaged, yet vasodilator responses were intact during rhythmic contractions indicating that cell-to-cell conduction along the endothelium is essential for ROV to ascend from arterioles into proximal feed arteries; (2) ROV is initiated primarily through endothelial cell hyperpolarization as evidenced by attenuated peak responses with K+ channel inhibition; and (3) vasodilatation during rhythmic exercise is a result of NO production in proximal feed arteries (as a result of elevated shear stress) secondary to metabolic dilatation within distal arterioles. Collectively, this study elegantly demonstrated that the vasodilator mechanisms that initiate exercise hyperaemia are not the same as those that sustain exercise hyperaemia. Contraction-induced ROV within humans has been observed in both the forearm and leg. Interestingly, this response is blunted with age (Hughes et al. 2016). At least within the forearm, both endothelial and neural factors have been implicated in age-associated reductions in ROV. In agreement with the notion that mechanisms involved in the initiation of exercise hyperaemia may not be the same as those that sustain it, Kirby et al. (2009) showed that in response to intra-arterial ascorbic acid (vitamin C), hyperaemic and vasodilator responses were augmented during rhythmic exercise in older adults primarily due to improvement in endothelial-dependent vasodilatation; however, ROV responses remained unchanged. Taken with the current data from Sinkler and Segal, it is obvious that there are distinct signalling events between the vasodilator signalling events at exercise onset and those during sustained rhythmic exercise; however, the integrity and functionality of the endothelium is critical. As such, a few questions and hypotheses emerge which may be addressed in the future to reconcile these discrepancies. First, examination of hyperaemic and vasodilator responses to a single skeletal muscle contraction is important as it permits interrogation of regulatory responses without the confounding influence of successive skeletal muscle contractions. Subsequently, examination of exercise onset (e.g. following a single skeletal muscle contraction) and transitions between exercise intensities may be more physiologically relevant as humans rarely operate at a steady-state response, yet rather are in a constant transition between workloads of varying metabolic costs. These may be investigated by examining the rate of adaptation or kinetics for hyperaemia/vasodilatation across the exercise transient (e.g. rest to steady state). Indeed, Casey et al. (2015) showed that within the forearm, older adults exhibit prolonged vasodilator kinetics relative to young adults, mediated in part by NO. In this context, the time course of blood flow adaptation during rhythmic exercise provides information into the ability of the vasculature to rapidly respond to increasing metabolic demands of contracting tissue. Do these complementary vasodilators work in concert from the onset of exercise into steady state? Evidence from the recent study by Sinkler and Segal suggests that when ROV is attenuated through endothelial damage, rhythmic responses are not impacted. However, when these vessels are exposed to combined inhibition of NOS and COX, vasodilatation within proximal feed arteries and 1A arterioles are significantly attenuated, yet vasodilatation within downstream arterioles remains intact. Second, ageing and chronic diseases are associated with endothelial dysfunction, concomitant to reductions in NO bioavailability. Given the findings of Sinkler and Segal, what is the effect of advancing age on the dynamic between vasodilator signalling at the onset of exercise and during steady-state exercise? Do the vasodilating pathways differ between young and older subjects? Furthermore, within the context of human data, exercise hyperaemia and vasodilatation have been observed to differ between limbs (e.g. arm vs. leg). Are these limb differences attributable to unique vasodilating pathways? In conclusion, Sinkler and Segal elegantly addressed a pressing question related to the regulation of skeletal muscle blood flow by showing that complementary signalling pathways are integral in the initiation and maintenance of exercise hyperaemia. Further research addressing whether these complementary signalling pathways are altered with age will bring about a new understanding within the realm of blood flow regulation. None declared. The author apologizes for not citing all relevant articles due to reference limitations. Extended gratitude goes to Dr Darren P. Casey for his critical evaluation and insightful comments for this manuscript.