Transcriptomic Analysis of the Mouse Retina after Acute and Chronic Normobaric and Hypobaric Hypoxia

Abstract

Purpose : Oxygen delivery to the outer retina through a continuous choroidal blood flow is crucial for cell metabolism, function, and survival. Mild but chronic conditions of reduced oxygen (hypoxia) can lead to retinal pathologies in patients, and a chronic hypoxic response in rods causes age-dependent retinal degeneration in mice. Apart from a decrease in inspired oxygen (normobaric hypoxia), hypoxia can be caused by exposure to reduced barometric pressure (hypobaric hypoxia). Since the cellular response to such chronic conditions is mostly unknown, we investigated the retinal transcriptome of mice kept for up to 11weeks in normobaric hypoxia and up to 7weeks in hypobaric hypoxia.

Methods : Wild type mice were exposed to normobaric hypoxia in a hypoxic chamber at 400m above sea level (asl) or to hypobaric hypoxia at the high-altitude research station on the Jungfraujoch (3450 masl). Bulk sequencing of retinal RNA was performed for 7 different conditions, ultimately (a) comparing acute and chronic hypoxia to normoxia, (b) investigating the adaptation to hypoxia over a timeframe of 6h, 48h and 11weeks, and (c) identifying differences between hypobaric and normobaric hypoxia. Additionally, length of photoreceptor segments was investigated.

Results : Retinas exposed to acute hypoxic conditions up-regulated gene sets involved in the response to oxygen levels, angiogenesis, ion transport, and programmed cell death. Differentially expressed genes in the hypoxic groups indicated a cellular adaptation process to chronic normobaric hypoxia. Based on their time-dependent response, we identified 23 genes which adapted within 48h and 40 genes which adapted after 11weeks of normobaric hypoxia. 7 genes however, showed an increased foldchange with prolonged exposure, suggesting that they might be key factors for phenotypic changes evoked by chronic hypoxia. A subset of 17 genes was regulated in hypobaric but not normobaric hypoxia. Shorter cone and rod segments were detected in some, but not all, hypoxic conditions.

Conclusions : This study identified differences in the genomic response to different levels and nature of hypoxia and presents data that (I) implies a high adaptability of mouse retina to chronic changes in inspired oxygen, (II) reveals differences in the retinal response to normobaric and hypobaric hypoxia, and (III) suggests that hypoxia may lead to a reduction in the length of photoreceptor segments.

This is a 2021 ARVO Annual Meeting abstract.