Neonatal stress and loss of ovarian hormones: a novel multidisciplinary approach to understand the coincidence of cardiorespiratory and metabolic disorders in females

Abstract

IntroductionIn women, the prevalence of sleep apnea (SA) rises 3‐fold at menopause and most patients also present hypertension and obesity. While the “protective effects” of ovarian hormones are well documented, we do not know why the loss of ovarian hormones leads to SA and related cardiovascular and metabolic disorders only in a subpopulation of women. Because neonatal stress is a major cause of adult diseases, we tested the hypothesis that loss of ovarian function reveals the latent effects of stress on cardiorespiratory and metabolic control. To do so, we subjected female rats to neonatal maternal separation (NMS), a translational model of early life stress.MethodologyRat pups subjected to NMS were placed in a temperature‐controlled incubator 3h/day from postnatal day 3 to 12; controls (CTRL) were undisturbed. The effects of loss of ovarian function were tested using a surgical approach (ovariectomy; OVX, animals with 8 weeks old) and aging (40 weeks old). Measurements of ventilation (by whole body plethysmography), blood pressure (by tail cuff plethysmography), and body composition (by nuclear magnetic resonance) were made. We also harvested brains from 8 weeks old females (SHAM versus OVX). Then, we compared the expression of FosB, a transcription factor that indicates neuronal activity. The number of FosB expressing neurons was counted in the paraventricular nucleus of the hypothalamus (PVH), the main structure regulating the hypothalamic pituitary adrenal (HPA) axis.ResultsNMS does not affect the incidence of apneic events in all groups. At 8 weeks, mean arterial pressure (MAP) of NMS females was 5% lower than CTRL. In addition, NMS females had 10% more body mass compared to CTRL. At 40 weeks, the MAP of NMS females was 15% higher than CTRL. In both ages, NMS presented 4% more fat, and 4% less lean tissue. OVX did not affect cardiorespiratory function but augmented the number of neurons expressing FosB in the PVH by 55% in NMS, not in CTRL females.DiscussionThe hypotension observed in young (8 weeks) NMS females was unexpected but is consistent with the fact that hypotension is a common comorbidity of depression. PVH dysfunction contributes to the increase of sympathetic vasomotor activity, characteristic of multiple forms of hypertension. Additionally, the chronic activation of the HPA axis can leads to obesity. The increased expression of FosB in OVX NMS animals indicate that ovarian hormones prevents the stress‐related rise of activity of the HPA axis. At 40 weeks old, the fact that NMS animals were obese and hypertensive indicates that those effects are age dependent. The emergence of dysregulation on the stress neuroaxis is a plausible mechanism to explain those results. Together, these data indicate that neonatal stress may explain why a subpopulation of women are at risk of developing cardiorespiratory and metabolic disturbance at menopause. Ongoing experiments will evaluate the incidence of SA in older animals (60 weeks old) and exploring the underlying mechanisms.