Sex-related differences in the peripheral vascular response to reflex coactivation: Fun physiology or window of opportunity?

Abstract

The carotid chemoreceptors are the body’s primary oxygen sensors. Located bilaterally at the bifurcation of the common carotid artery, they are well-situated to sense changes in arterial partial pressure of oxygen and elicit necessary reflex responses (e.g. hyperventilation). In addition to their known oxygen-sensing capabilities, the carotid chemoreceptors play an important role in the integrative cardiovascular response to exercise. Indeed, activity of the sympathetic nervous system increases with exercise and at least a portion of sympathetic vasoconstrictor tone can be attributed to the chemoreceptors. The role for the carotid chemoreceptors in the sympathetic response to exercise becomes particularly relevant in the context of clinical conditions such as hypertension, heart failure and perhaps even diabetes. In both pre-clinical models and human patients with heart failure, the contribution of the carotid chemoreceptors to sympathetic vasoconstrictor tone is evident even at rest. Inhibition of chemoreceptor activity can further improve cardiovascular regulation during exercise in heart failure (Collins et al., 2020). The mechanisms by which this may be occurring are many and include interactions between the exercise pressor reflex (i.e. mechanoand metaboreflex) and the carotid chemoreceptors (Edgell & Stickland, 2014). Thus, chemoreceptor activation in the context of exercise may potentiate cardiovascular consequences of such conditions. Notably, the metaboreflex was recently identified to contribute to enhanced peripheral vasoconstriction in patients with heart failure (Barrett-O’Keefe et al., 2018). When considered clinically, exaggerated sympathetically-mediated vasoconstriction in the context of exercise is not limited to the skeletal muscle circulation and has similarly been observed at the level of the kidney. Although this work has been shown to provide comparable results across species (e.g. dogs, humans), less is known regarding the translation of findings across sexes. A lack of understanding of sex-related differences in reflex interactions is primarily a result of the tendency of prior work to include only males or a very small proportion of females. As a result, sex-related differences have only recently been identified and remain poorly described in clinical cohorts. In the most recent issue of The Journal of Physiology, Wan et al. (2022) tested the hypothesis that reflex interactions between the muscle mechanoreflex (passive limb movement) and chemoreflex (hypoxia, hypercapnia) would restrict vascular conductance and blood flow in male but not female adults – attributed to effects of sympathetic activity on the peripheral vasculature. Although not a primary focus, a previous post hoc analysis of a mixed-sex cohort conducted by this group (Wan et al., 2020) found that the leg blood flow response to combined activation of the exercise pressor and chemoreflexes did not differ between male and female participants. However, as noted above, the exercise pressor reflex is the combined response to both metaboreflex and mechanoreflex activation. Including matched groups of male and female participants, Wan et al. (2022) found the mechanoreflex and chemoreflex interact to restrain peripheral hemodynamics in male adults, consistent with their prior published data (Wan et al., 2020). By contrast, these same reflex interactions in a group of healthy, normal weight, pre-menopausal, female adults potentiated peripheral vasodilatation. Wan et al. (2022) conclude ‘the interaction of the mechanoreflex and chemoreflex has a pronounced influence on the autonomic cardiovascular control, with the hemodynamic consequences differing between men and women’. Unfortunately, direct recordings of muscle sympathetic nerve activity, which are understandably difficult to perform, were not included, and thus it is difficult to comment on whether the sympathetic stimulus was comparable between groups. Regardless, the peripheral vascular (leg blood flow) response to reflex coactivation differed significantly between the sexes. As a cardiovascular physiologist trained in exercise physiology and enamoured by the autonomic nervous system, exploring and uncovering unique and divergent reflex responses using creative experimental approaches is fun to think about and enjoyable to read. Advancing knowledge is a tenant of our profession. With this, it is also essential that we review these data through the lens of ‘what’s next?’ The results obtained by Wan et al. (2022) highlight that the same environmental stressors have the potential to elicit differing signs and symptoms in male vs. female adults. In the context of ‘health’, as alluded by Wan et al. (2022), it would be interesting to advance this work at altitude where exercise and chemoreflex activation coincide and where the majority of work has been conducted in a convenience sample of primarily young, healthy male adults. It is also important to consider how the results of Wan et al. (2022) may directly impact individuals living with chronic conditions known to exhibit exaggerated mechanoand/or chemoreflexes (i.e. heart failure, hypertension, diabetes) but where the data come from cohorts of primarily male participants. Based on present results published in The Journal of Physiology, this same phenotype may not be observed in female participants/patients. With this, it is also important to acknowledge that females studied presently were pre-menopausal, apparently healthy of normal weight and without common comorbidities (e.g. high blood pressure, fasting hyperglycaemia, hyperinsulinaemia, central adiposity). How such comorbid factors interplay with the ‘normal’ physiological response in female adults, as well as the impact of changes in hormonal milieu (e.g. pregnancy, menopause, hormone replacement therapy), remain to be