Intermittent Hypoxia Promotes Functional Neuroprotection from Retinal Ischemia in Untreated First-Generation Offspring: Proteomic Mechanistic Insights

Abstract

Purpose Stress can lead to short- or long-term changes in phenotype. Accumulating evidence also supports the transmission of maladaptive phenotypes, induced by adverse stressors, through the germline to manifest in subsequent generations, providing a novel mechanistic basis for the heritability of disease. In the present study in mice, we tested the hypothesis that repeated presentations of a nonharmful conditioning stress, demonstrated previously to protect against retinal ischemia, will also provide ischemic protection in the retinae of their untreated, first-generation (F1) adult offspring. Methods Swiss–Webster ND4 outbred mice were mated following a 16-week period of brief, every-other-day conditioning exposures to mild systemic hypoxia (repetitive hypoxic conditioning, RHC). Retinae of their 5-month-old F1 progeny were subjected to unilateral ischemia. Scotopic electroretinography quantified postischemic outcomes. The injury-resilient retinal proteome was revealed by quantitative mass spectrometry, and bioinformatic analyses identified the biochemical pathways and networks in which these differentially expressed proteins operate. Results Significant resilience to injury in both sexes was documented in F1 mice derived from RHC-treated parents, relative to matched F1 adult progeny derived from normoxic control parents. Ischemia-induced increases and decreases in the expression of many visual transduction proteins that are integral to photoreceptor function were abrogated by parental RHC, providing a molecular basis for the observed functional protection. Conclusions Our proteomic analyses provided mechanistic insights into the molecular manifestation of the inherited, injury-resilient phenotype. To our knowledge, this is the first study in a mammalian model documenting the reprogramming of heritability to promote disease resilience in the next generation.

Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

“…We have shown previously in mice that repetitive hypoxic preconditioning (RHC) induces a long-lasting resilience to acute stroke (Stowe et al, 2011). More recently, we documented that untreated, first-generation adult progeny of mice exposed to RHC prior to mating are protected from retinal ischemic injury (Harman et al, 2020), consistent with accumulating evidence supporting the concept that long-lasting phenotypes induced epigenetically by intermittent stressors may be heritable. We undertook the present study to test the hypothesis that RHC will induce resilience to VCID, and that such RHC-induced resilience can also be inherited.…”

“…We have shown previously in mice that repetitive hypoxic preconditioning (RHC) induces a long-lasting resilience to acute stroke (Stowe et al, 2011). More recently, we documented that untreated, first-generation adult progeny of mice exposed to RHC prior to mating are protected from retinal ischemic injury (Harman et al, 2020), consistent with accumulating evidence supporting the concept that long-lasting phenotypes induced epigenetically by intermittent stressors may be heritable. We undertook the present study to test the hypothesis that RHC will induce resilience to VCID, and that such RHC-induced resilience can also be inherited.Methods: Chronic cerebral hypoperfusion (CCH) was induced in C57BL/6J mice secondary to bilateral carotid artery stenosis with microcoils in both the parental (F0) generation, and in their untreated first-generation (F1) offspring.Cohorts of F0 mice were directly exposed to either 8 wks of RHC (1 h of systemic hypoxia [11% oxygen] 3x/week) or normoxia prior to CCH.…”

“…Importantly, our lab has also documented, in a mouse model of focal stroke, that the duration of this inducible neurovascular-protective phenotype can be extended dramatically - from days to months - following the last of a series of repetitive hypoxic conditioning (RHC) stimuli (Stowe et al, 2011). In a recent study, we showed that 4 months of RHC in male and female mice, prior to breeding, results in a heritable resilience to retinal ischemic injury in their untreated, first-generation progeny (Harman et al, 2020).…”

Epigenetic conditioning induces intergenerational resilience to dementia in a mouse model of vascular cognitive impairment

“…9 Recently, we showed that 4 months of RHC in male and female mice, prior to breeding, results in a heritable resilience to retinal ischemic injury in their untreated, first-generation progeny. 12 Although a number of studies have provided evidence for intergenerational epigenetic inheritance in both animals and humans, 13,14 the vast majority have focused on the heritability of disease risk and disease itself. In the present investigation, we hypothesized that RHC will induce resilience to cognitive deficits in a mouse model of VCID, and that this dementia-resilient phenotype will be inherited.…”

Editorial: RNA-Mediated Processes in Epigenetics; an Integrative View in the Maintenance of Homeostasis

“…In the literature, Harman et al ( 2020 ) are proposing the first demonstration documenting the reprogramming of heritability in mammals to promote disease resilience in the next generation. A beneficial link of stress on the F1 generation connected with some miRNA pathway has been described on a mouse model of ophthalmic care.…”