Roles of oestradiol receptor alpha and beta against hypertension and brain mitochondrial dysfunction under intermittent hypoxia in female rats

Abstract

Aim Chronic intermittent hypoxia (CIH) induces systemic (hypertension) and central alterations (mitochondrial dysfunction underlying cognitive deficits). We hypothesized that agonists of oestradiol receptors (ER) α and β prevent CIH‐induced hypertension and brain mitochondrial dysfunction. Methods Ovariectomized female rats were implanted with osmotic pumps delivering vehicle (Veh), the ERα agonist propylpyraoletriol (PPT — 30 μg/kg/day) or the ERβ agonist diarylpropionitril (DPN — 100 μg/kg/day). Animals were exposed to CIH (21%‐10% FIO2 — 10 cycles/hour – 8 hours/day – 7 days) or normoxia. Arterial blood pressure was measured after CIH or normoxia exposures. Mitochondrial respiration and H2O2 production were measured in brain cortex with high‐resolution respirometry, as well as activity of complex I and IV of the electron transport chain, citrate synthase, pyruvate, and lactate dehydrogenase (PDH and LDH). Results Propylpyraoletriol but not DPN prevented the rise of arterial pressure induced by CIH. CIH exposures decreased O2 consumption, complex I activity, and increased H2O2 production. CIH had no effect on citrate synthase activity, but decreased PDH activity and increased LDH activity indicating higher anaerobic glycolysis. Propylpyraoletriol and DPN treatments prevented all these alterations. Conclusions We conclude that in OVX female rats, the ERα agonist prevents from CIH‐induced hypertension while both ERα and ERβ agonists prevent the brain mitochondrial dysfunction and metabolic switch induced by CIH. These findings may have implications for menopausal women suffering of sleep apnoea regarding hormonal therapy.

Progesterone decreases apnoea and reduces oxidative stress induced by chronic intermittent hypoxia in ovariectomized female rats

“…On the other hand, Prog does not prevent the CIH‐induced increase in arterial blood pressure. These results complement our previous dataset showing the role of E 2 (Laouafa et al., 2017; Ribon‐Demars et al., 2018) and selective agonists of E 2 receptors (Laouafa et al., 2019) on oxidative stress, respiratory irregularities and arterial blood pressure in a similar experimental design.…”

“…One may therefore speculate that during CIH exposure Prog prevents oxidative stress in the peripheral chemoreflex pathway, thereby preventing the high activity and elevation of the hypoxic ventilatory response. Contrasting with the effects of E 2 (Laouafa et al., 2019), Prog also decreased the hypercapnic ventilatory response, suggesting additional effects on central chemoreceptors. Because high activity of the peripheral chemoreceptors contributes to the development of arterial hypertension (Prabhakar et al., 2015), it is surprising that Prog does not reduce MAP in our experiments.…”

“…In the peripheral chemoreceptors, CIH exposure for 10 days increases the expression of the NADPH oxidase family members Nox1, Nox2 and Nox3 (Khan et al., 2011; Peng et al., 2009; Prabhakar et al., 2015) and the activity of complex I of the mitochondrial electron transport chain is reduced (Peng et al., 2003), leading to enhanced cytosolic and mitochondrial ROS production. We have reported that CIH exposure reduced the activity of mitochondrial complex I and increased mitochondrial H 2 O 2 production in the brain cortex of OVX female rats exposed to CIH, and that selective agonists for ERα and ERβ could prevent these effects (Laouafa et al., 2019). Interestingly, Prog, similar to E 2 , is known for its antioxidant properties, and for a potential role to prevent exaggerated mitochondrial production of reactive oxygen species (Gaignard et al., 2016, 2017).…”

“…In line with a rich literature showing antioxidant properties of E 2 , we have demonstrated that in female rats exposed to CIH, E 2 supplementation prevented the elevation of arterial blood pressure and oxidative stress damage in the brain cortex, brainstem (Laouafa et al., 2017) and thoracic aorta (Ribon‐Demars et al., 2018). Furthermore selective agonists of the E 2 α and β receptors (ERα and ERβ) prevented the elevation of mitochondrial ROS production during CIH exposure, but only the ERα agonist prevented the increase of arterial blood pressure (Laouafa et al., 2019). Progesterone has also neuroprotective and antioxidant effects in several animal models of brain injury such as stroke or hypoxia/ischaemia (Cervantes, Gonzalez‐Vidal, Ruelas, Escobar, & Morali, 2002; Singh & Su, 2013).…”

Recent advances in blood pressure research

“…Investigating the mechanisms of blood pressure regulation was again a focus of a number of articles published in Acta physiologica in the recent year. The research on basic physiological questions and mechanism in model organisms is complemented with studies that include clinical patient data …”