Sex‐specific Consequences of Psychosocial Stress on Cardiorespiratory Control: a Comparison with Intermittent Hypoxia

Abstract

Sleep apnea (SA) is a complex, multifactorial and a sex‐specific respiratory disorder; sexual dimorphism being present both in its prevalence and in the presentation of the pathology. To this day, the origins of SA remain unknown. While intermittent hypoxia (IH) is commonly used to assess the pathophysiology of SA, this systemic stress is a consequence, not a cause of SA. The psychosocial stress of social isolation (SI) and the recent COVID pandemic showed how SI increases the risk for a broad range of diseases, including hypertension and obesity, which are common comorbidities of SA. While there is growing evidence linking psychosocial stress and SA, its effect on cardiorespiratory function is yet to be established. To address this issue, we tested the hypothesis that SI is sufficient to induce sex‐specific cardiorespiratory and metabolic disturbances similar to those seen in patients with SA. We then compared the effects of SI with those observed following moderate IH.Adult (8 weeks old) rats were subjected to either three weeks of social isolation or standard housing. SI consisted of single housing without visual contact with other rats (n = 22); the control rats were housed in pairs (n = 22), both groups under normoxic conditions. The third group (n = 18) housed in pairs was exposed to intermittent hypoxia (IH: FiO2 = 0.10 – 30s, 10 cycles/hour, 8 hours/day, 7 days). Apneas were quantified by whole body plethysmography during sleep. Cardiovascular measurements were then measured by tail cuff pressure and body composition by magnetic resonance. Blood samples were obtained at the end of the protocol to measure plasma corticosterone and ACTH with a multiplex assay.Male rats subjected to SI had an apnea index 27% higher than controls, were hypertensive (+ 15mmHg) and gained 6% more weight than males in pair housing. The body fat and fluid gains of SI males were, respectively, 21% and 38% higher than their controls. Yet, food consumption did not differ between the two groups. SI augmented plasma ACTH and corticosterone. The SI protocol had no significant effect in females. IH males (but not females) were hypertensive (+ 9mmHg), and their heart rate was 54 bpm greater than controls but no significant change in the number of apneas. Moderate IH did not augment stress hormone levels. Unlike SI, IH reduced food consumption and weight gain in both sexes. IH reduced body fat by 18% and body fluids by 30% compared to controls. Body composition of IH females was not different from controls.Our results demonstrate that SI is sufficient to activate the neuroendocrine stress response and induce sex‐specific cardiorespiratory and metabolic disturbances similar to those reported in SA patients. Our observations also suggest that the cardiovascular disturbance in IH occurs before respiratory disruption, and that and the activation of the stress pathways is necessary to augment apneic events. A longer or more severe protocol should be considered. These results indicate that stress hormones play an important role in the etiology of respiratory disorders and key comorbidities such as hypertension and obesity. We propose that SI is a valuable model to investigate the origins and pathophysiology of SA.