Chronic developmental hypoxia alters mitochondrial oxidative capacity and reactive oxygen species production in the fetal rat heart in a sex‐dependent manner

Abstract

Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodeling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex‐dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured the sex‐dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, reactive oxygen species (ROS) production, and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13% oxygen) during gestational days (GDs) 6–20 (term ~22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On GD 20, mitochondrial aerobic respiration and H2O2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase (CS) activity. Gestational hypoxia reduced maternal body weight gain (p < .01) and increased placental weight (p < .05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at Complex II (CII) (p < .05), and an increase in H2O2 production/O2 consumption (p < .05) without any changes in lipid peroxidation. CS activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration (p < .001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex‐dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies.

Intermittent hypoxia-induced enhancement of sociability and working memory associates with CNTNAP2 upregulation

“…Furthermore, results from the Morris Water Maze showed that female mice’s spatial learning and memory were more vulnerable to hypoxia exposure. Of note, an article mentions that hypoxia decreased the capacity of Complex II respiratory in male fetuses only, indicating a sex-dependent effect ( Smith et al, 2022 ). Snyder et al reported that androgens modulate chronic intermittent hypoxia’s effects on the brain and behavior ( Snyder et al, 2018 ), which may underlie the sex difference in sociability and memory observed in our study.…”

Adapting to a new environment: postnatal maturation of the human cardiomyocyte

“…Metabolic remodelling becomes necessary to support the increased demand on the developing heart, as fatty acid oxidation yields more ATP (per unit substrate) compared with glycolysis. The time frame and mechanisms underlying this metabolic switch are underexplored in humans, but in rodent models, studies suggest that this process is influenced by the increase in ambient oxygen at birth and the subsequent reduction in (Botting et al, 2014;Smith et al, 2022;Song et al, 2021). In humans, cyanotic congenital heart disease can disrupt postnatal maturation, because chronic hypoxia results in elevated HIF1α and persistent glucose-dominated cardiac metabolism in paediatric patients (Horikoshi et al, 2019;Liu et al, 2021;Piccoli et al, 2017;Porter et al, 2011;Quing et al, 2007).…”

“…hypoxia‐inducible factor‐1α (HIF1α) and HAND1; Liu et al., 2021; Neary et al., 2014]. Chronic hypoxic conditions have been shown to dysregulate metabolic remodelling in rodents and impair heart development in sheep by reducing the total number of cardiomyocytes (Botting et al., 2014; Smith et al., 2022; Song et al., 2021). In humans, cyanotic congenital heart disease can disrupt postnatal maturation, because chronic hypoxia results in elevated HIF1α and persistent glucose‐dominated cardiac metabolism in paediatric patients (Horikoshi et al., 2019; Liu et al., 2021; Piccoli et al., 2017; Porter et al., 2011; Quing et al., 2007).…”

Melatonin ameliorates myocardial infarction in obese diabetic individuals: The possible involvement of macrophage apoptotic factors

“…In fact, recently researchers have strengthened the idea of melatonin administration as a potent antioxidizing therapeutic agent withstanding pregnancy-related complications. 88 MLT, a potent antioxidant, 89 accelerates the activity of other antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR). 90 It works in coordination with reduced glutathione (GSH), NADPH, vitamin C, and vitamin E. Besides, melatonin via melatonin receptor 1 (MT1) could potentially block the F I G U R E 1 Summarization of potential effects of obesity-diabetes linkage mediated oxidative stress-induced and inflammatory response aggravated damages in cardiac cells.…”

“…Several studies have supported melatonin administration as it produces negligible or rather no toxicity in permissible doses and can be used for the prevention, treatment, and recovery of obesity and diabetes‐induced OS‐mediated changes in the heart. In fact, recently researchers have strengthened the idea of melatonin administration as a potent antioxidizing therapeutic agent withstanding pregnancy‐related complications 88 …”