Estrogen receptor alpha determines sex-specific cardiorespiratory and autonomic responses to intermittent hypoxia in mice

Despite the evidence that responses to intermittent hypoxia (IH) vary between sexes, potentially underlying sex-specific comorbidities of sleep apnea, the roles that sex hormones play during exposure to IH in rodent models remain poorly defined. The estradiol receptor α (ERα), expressed in structures of the peripheral and central nervous system, contributes to autonomic regulations and control of arterial blood pressure; accordingly, we tested the hypothesis that ERα modulates respiratory and heart rate variability in male and female mice exposed to IH. We used adult wild-type (WT) and ERα knockout (ERαKO) mice of both sexes for whole body plethysmography, arterial blood pressure, and ECG recordings before and after 14 days of IH (6% O₂, 12 cycles/h, 12 h/day). Compared with males, WT females exhibited greater respiratory variability and higher apnea frequency before IH exposure. In females, ERα deletion increased body weight and reduced postsigh apnea frequency before IH exposure. In ANCOVA/GLM models, body weight was a significant negative covariate for postsigh and spontaneous apneas before IH exposure, whereas sex and genotype effects were not significant after adjustment. IH exposure increased the mean and diastolic blood pressures only in WT males. IH also increased apneas frequency in WT females, an effect markedly reduced by ERα deletion. Similarly, heart rate variability increased in WT females following IH, reflecting enhanced parasympathetic modulation, an effect absent in ERαKO females and in WT or ERαKO males. We conclude that in female mice, deletion of ERα prevents IH-induced improvement of heart rate variability.<b>NEW & NOTEWORTHY</b> We show that <i>1</i>) the intrinsic variability of the breathing pattern and the frequency of apneas both before and after exposure to intermittent hypoxia (IH) are higher in WT female mice compared with males, <i>2</i>) higher body weight is significantly associated with lower apnea frequency in ERαKO female mice, and <i>3</i>) in female mice, the expression of ERα appears to be essential to increase heart rate variability following exposure to IH.