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Mitochondria-derived oxidative stress during fetal development increases cardiovascular risk in adult offspring of pregnancies complicated by chronic fetal hypoxia. We investigated the efficacy of the mitochondria-targeted antioxidant MitoQ in preventing cardiovascular dysfunction in adult rat offspring exposed to gestational hypoxia, integrating functional experiments in vivo, with those at the isolated organ and molecular levels. Rats were randomized to normoxic or hypoxic (13%-14% O2) pregnancy ± MitoQ (500 μM day-1) in the maternal drinking water. At 4 months of age, one cohort of male offspring was chronically instrumented with vascular catheters and flow probes to test in vivo cardiovascular function. In a second cohort, the heart was isolated and mounted onto a Langendorff preparation. To establish mechanisms linking gestational hypoxia with cardiovascular dysfunction and protection by MitoQ, we quantified the expression of antioxidant system, β-adrenergic signaling, and calcium handling genes in the fetus and adult, in frozen tissues from a third cohort. Maternal MitoQ in hypoxic pregnancy protected offspring against increased α1-adrenergic reactivity of the cardiovascular system, enhanced reactive hyperemia in peripheral vascular beds, and sympathetic dominance, hypercontractility and diastolic dysfunction in the heart. Inhibition of Nfe2l2-mediated oxidative stress in the fetal heart and preservation of calcium regulatory responses in the hearts of fetal and adult offspring link molecular mechanisms to the protective actions of MitoQ treatment of hypoxic pregnancy. Therefore, these data show the efficacy of MitoQ in buffering mitochondrial stress through NADPH-induced oxidative damage and the prevention of programmed cardiovascular disease in adult offspring of hypoxic pregnancy. [ABSTRACT FROM AUTHOR]

Antenatal glucocorticoid therapy reduces mortality in the preterm infant, but evidence suggests off‐target adverse effects on the developing cardiovascular system. Whether deleterious effects are direct on the offspring or secondary to alterations in uteroplacental physiology is unclear. Here, we isolated direct effects of glucocorticoids using the chicken embryo, a model system in which the effects on the developing heart and circulation of therapy can be investigated, independent of effects on the mother and/or the placenta. Fertilized chicken eggs were incubated and divided randomly into control (C) or dexamethasone (Dex) treatment at day 14 out of the 21‐day incubation period. Combining functional experiments at the isolated organ, cellular and molecular levels, embryos were then studied close to term. Chicken embryos exposed to dexamethasone were growth restricted and showed systolic and diastolic dysfunction, with an increase in cardiomyocyte volume but decreased cardiomyocyte nuclear density in the left ventricle. Underlying mechanisms included a premature switch from tissue accretion to differentiation, increased oxidative stress, and activated signaling of cellular senescence. These findings, therefore, demonstrate that dexamethasone treatment can have direct detrimental off‐target effects on the cardiovascular system in the developing embryo, which are independent of effects on the mother and/or placenta. [ABSTRACT FROM AUTHOR]