Abstract
Oxygen delivery to the retinal pigment epithelium and the outer retina is essential for metabolism, function, and survival of photoreceptors. Chronically reduced oxygen supply leads to retinal pathologies in patients and causes age-dependent retinal degeneration in mice. Hypoxia can result from decreased levels of inspired oxygen (normobaric hypoxia) or reduced barometric pressure (hypobaric hypoxia). Since the response of retinal cells to chronic normobaric or hypobaric hypoxia is mostly unknown, we examined the effect of six hypoxic conditions on the retinal transcriptome and photoreceptor morphology. Mice were exposed to short- and long-term normobaric hypoxia at 400 m or hypobaric hypoxia at 3450 m above sea level. Longitudinal studies over 11 weeks in normobaric hypoxia revealed four classes of genes that adapted differentially to the hypoxic condition. Seventeen genes were specifically regulated in hypobaric hypoxia and may affect the structural integrity of the retina, resulting in the shortening of photoreceptor segment length detected in various hypoxic groups. This study shows that retinal cells have the capacity to adapt to long-term hypoxia and that consequences of hypobaric hypoxia differ from those of normobaric hypoxia. Our datasets can be used as references to validate and compare retinal disease models associated with hypoxia.
Highlights
Oxygen delivery to the retinal pigment epithelium and the outer retina is essential for metabolism, function, and survival of photoreceptors
In contrast to potential long-term adaptation of people living in the highlands, ascent to high altitude by a non-acclimatized person can cause acute mountain sickness[11], memory loss, high-altitude cerebral edema[12], and high-altitude retinopathy that belongs to the group of hypoxia-regulated d iseases[13]
Four experimental groups were set to analyze transcriptomic changes during normobaric hypoxia of varying levels (7% or 14% O 2) and duration (6 h, 48 h, and 11 weeks), and two groups were evaluated in hypobaric hypoxia after exposure to reduced barometric pressure (at 3450 m above sea level) for 48 h or 7 weeks (Table 1)
Summary
Oxygen delivery to the retinal pigment epithelium and the outer retina is essential for metabolism, function, and survival of photoreceptors. Reduced oxygen supply leads to retinal pathologies in patients and causes age-dependent retinal degeneration in mice. Since the response of retinal cells to chronic normobaric or hypobaric hypoxia is mostly unknown, we examined the effect of six hypoxic conditions on the retinal transcriptome and photoreceptor morphology. This study shows that retinal cells have the capacity to adapt to long-term hypoxia and that consequences of hypobaric hypoxia differ from those of normobaric hypoxia. Diseases affecting the choriocapillaris and/or the central retinal artery lead to pathological changes including reduced vessel diameter, as well as decreased velocity and oxygen-carrying capacity of red blood cells, resulting in reduced tissue oxygenation (hypoxia). Since reduced tissue oxygenation and the resulting pathological processes are implicated in many retinal diseases, more insights into the cellular response to acute and chronic hypoxia are necessary to better understand. The impact of different hypoxic conditions on photoreceptor segment length was evaluated
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