Sex differences in the activation of central autonomic control regions and neuroinflammation in chronic intermittent hypoxia

Purpose: Obstructive sleep apnea (OSA) is an independent risk factor for hypertension. Chronic interment hypoxia (CIH), which models episodic hypoxemia of OSA, produces daytime hypertension, oxidative stress, and activation of central autonomic regions that regulate mean arterial pressure (MAP) in male Sprague Dawley (SD) rats. Unlike gonadally intact females, gonadectomized females and males develop CIH hypertension. Lesioning of median preoptic nucleus (MnPO) in males prevents CIH hypertension. We hypothesize that the sex difference observed in CIH hypertension is due sex differences in neuroinflammation and activation of central autonomic regions that support MAP in CIH. Methods: Gonadally intact adult male and female SD rats (250-300g) were continuously exposed to normoxia (CON) or CIH (10% O2 every 3mins cycling 21% O2 every 3mins, 8h/day) for 7 days. Radiotelemetry transmitters were implanted in rats to record MAP and heart rate (HR). After one week of baseline recording, the rats were exposed to either continuous normoxia or CIH and were euthanized (inactin 100 mg/kg ip) on the 8th day for immunohistochemistry and blood analysis. All forebrain sections were stained for FosB/ΔFosB and either neuronal nitric oxide synthase (NOS1) or IBA1 to identify active microglia. Results: CIH males exhibited significantly increased hematocrit indicating erythropoiesis compared to control males (CON 42.1% ± 0.6, n=10; CIH 44.6% ± 0.7, n = 10. P = 0.0173). CIH males exhibited an increase in the average number of FosB positive neurons (CON male 20 ± 2 cells/section, CIH male 35 ± 3; CON female 11 ± 1, CIH female 12 ± 2,) and colocalization of FosB and NOS1 (CON male 10 ± 1 cells/section, CIH male 18 ± 4; CON female 5 ± 1, CIH female 6 ± 1) in the MnPO. CIH females showed a trend for an increase in the average number of IBA1 immunoreactive microglial cells in MnPO (CON 187 ± 16, n = 2; CIH 218 ± 18, n = 4). Conclusion: CIH is associated with increased FosB staining in the MnPO of male rats as opposed to female rats which is consistent with our working hypothesis. In addition, FosB positive MnPO neurons also contained NOS1. In female rats, CIH is associated with a trend for an increase in the numbers of IBA1 positive microglia, indicating increased neuroinflammation in females that is independent of hypertension. CIH was associated with increased FosB staining in NOS1 positive MnPO neurons suggesting that they may be contributing to the sustained hypertension reported in male rats.

The research is funded by NIH grant RO1 HL155977.