Chronic intermittent hypoxia modulates fibrosis and hormone receptor expression in the rat cornea

Abstract

Purpose : Chronic intermittent hypoxia (CIH) is a commonly observed condition in patients suffering from obstructive sleep apnea (OSA). Clinically, women and men present different symptoms and have varying pathophysiology associated with OSA diagnosis. Previous studies link CIH to hormonal dysregulation, and fibrosis across various tissues; however, there is no evidence demonstrating an effect of CIH in the cornea and whether sex is a modifier of these effects. This study aims to assess the impact of CIH and sex on fibrosis and hormone receptor expressions in the rat cornea.

Methods : Male and female adult Sprague Dawley rats underwent either Normoxic or CIH conditions during 8 hours/day of their sleep cycle for 14 days. The CIH protocol consisted of 6-minute cycles (3 minutes of hypoxia at 10% O₂ and 3 minutes of normoxia at 21% O₂). Rats were sacrificed on day 14, corneas were extracted, and corneal proteins were subjected to western blot analysis.

Results : The overall comparison between Normoxic and CIH revealed no significant difference in the fibrotic markers tested (Col III, SMA, cFN, TsP1). However, sex-specific differences were observed: Col III was higher in Female-Normoxic rats compared to Male-Normoxic rats, and cFN was consistently elevated in Female-Normoxic rats and Female-CIH rats compared to Male-normoxic and Male-CIH respectively. Significant changes in SMA was also observed, with an increase in Female-CIH rats compared to Male-CIH rats and significantly higher levels in Female-CIH rats compared to Female-Normoxic rats. Results also revealed distinctive patterns in hormone receptor expression in the cornea. CIH decreased ER-β, GnRH-r and LH-R expression in the cornea, however, these effects were dependent on sex, in which CIH suppression of ER-β and GnRH-R occurred in female rats and LH-R suppression occurred in male rats. Finally, LH-R showed higher expression in Male-Normoxic rats compared when compared to Female-Normoxic rats.

Conclusions : These findings indicate a sex-dependent response to CIH, influencing corneal fibrosis and hormone receptor expression. The downregulation of ER-β under CIH conditions requires further investigation into its potential role in the cornea. Additionally, the sex-specific variations in fibrotic markers and hormone receptors underscore the intricate interplay between hormonal regulation and CIH-induced effects.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.