Maternal treatment with a placental-targeted antioxidant (MitoQ) impacts offspring cardiovascular function in a rat model of prenatal hypoxia

Aljunaidy, Mais M.; Morton, Jude S.; Kirschenman, Raven; Phillips, Tom J.; Case, C. P.; Cooke, Christy Lynn M.; Davidge, Sandra T.

doi:10.1016/j.phrs.2018.05.006

Cited by 47 publications

(37 citation statements)

References 34 publications

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“…Previous studies using ex vivo techniques to assess cardiac function in offspring exposed to prenatal HPX report a decrease in recovery following ischemia-reperfusion injury (32,58), cardiac ␤-adrenergic receptor signaling (46), and diastolic function (7). In addition, gestational hypoxia has variable effects on ventricular wall mass (32), causing increased hypertrophic growth or no change, depending on the animal model.…”

Section: Discussionmentioning

confidence: 99%

Prenatal hypoxia impairs cardiac mitochondrial and ventricular function in guinea pig offspring in a sex-related manner

Thompson

Chen

Polster

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Adverse intrauterine conditions cause fetal growth restriction and increase the risk of adult cardiovascular disease. We hypothesize that intrauterine hypoxia impairs fetal heart function, is sustained after birth, and manifests as both cardiac and mitochondrial dysfunction in offspring guinea pigs (GPs). Pregnant GPs were exposed to 10.5% O2 (HPX) at 50 days of gestation (full term = 65 days) or normoxia (NMX) for the duration of the pregnancy. Pups were allowed to deliver vaginally and raised in a NMX environment. At 90 days of age, mean arterial pressure (MAP) was measured in anesthetized GPs. NMX and prenatally HPX offspring underwent echocardiographic imaging for in vivo measurement of left ventricular cardiac morphology and function, and O2 consumption rates and complex IV enzyme activity were measured from isolated cardiomyocytes and mitochondria, respectively. Prenatal HPX increased ( P < 0.01) MAP (52.3 ± 1.3 and 58.4 ± 1.1 mmHg in NMX and HPX, respectively) and decreased ( P < 0.05) stroke volume (439.8 ± 54.5 and 289.4 ± 15.8 μl in NMX and HPX, respectively), cardiac output (94.4 ± 11.2 and 67.3 ± 3.8 ml/min in NMX and HPX, respectively), ejection fraction, and fractional shortening in male, but not female, GPs. HPX had no effect on left ventricular wall thickness or end-diastolic volume in either sex. HPX reduced mitochondrial maximal respiration and respiratory reserve capacity and complex IV activity rates in hearts of male, but not female, GPs. Prenatal HPX is a programming stimulus that increases MAP and decreases cardiac and mitochondrial function in male offspring. Sex-related differences in the contractile and mitochondrial responses suggest that female GPs are protected from cardiovascular programming of prenatal HPX.

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Section: Discussionmentioning

confidence: 99%

Prenatal hypoxia impairs cardiac mitochondrial and ventricular function in guinea pig offspring in a sex-related manner

Thompson

Chen

Polster

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Female rats were mated overnight and pregnancy was confirmed the following morning by the presence of sperm in the vaginal smear (defined as gestational day (GD) 0 of pregnancy). Based on previous studies (Phillips et al., 2017; Aljunaidy et al., 2018; Ganguly et al., 2019), on GD15, pregnant dams were randomly assigned into two groups that received a single intravenous injection (100 μl) via the tail vein with either saline or nMitoQ (125 μ m ). The nanoparticles are composed of poly γ‐glutamic acid and an l ‐phenylalanine ethyl ester and were synthesized as previously described (Phillips et al., 2017; Aljunaidy et al., 2018; Ganguly et al., 2019).…”

Section: Methodsmentioning

confidence: 99%

“…Based on previous studies (Phillips et al., 2017; Aljunaidy et al., 2018; Ganguly et al., 2019), on GD15, pregnant dams were randomly assigned into two groups that received a single intravenous injection (100 μl) via the tail vein with either saline or nMitoQ (125 μ m ). The nanoparticles are composed of poly γ‐glutamic acid and an l ‐phenylalanine ethyl ester and were synthesized as previously described (Phillips et al., 2017; Aljunaidy et al., 2018; Ganguly et al., 2019). We have previously demonstrated that nanoparticles alone are inert; hence, our treatment consisted of nMitoQ as a single entity, with saline as control (Phillips et al., 2017).…”

Section: Methodsmentioning

confidence: 99%

Placenta‐targeted treatment in hypoxic dams improves maturation and growth of fetal cardiomyocytes in vitro via the release of placental factors

Ganguly

Spaans

Morton

et al. 2020

Experimental Physiology

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New Findings What is the central question of this study?Does treatment of hypoxic dams with a placenta‐targeted antioxidant prevent the release of placenta‐derived factors that impair maturation or growth of fetal cardiomyocytes in vitro? What is the main finding and its importance?Factors released from hypoxic placentae impaired fetal cardiomyocyte maturation (induced terminal differentiation) and growth (increased cell size) in vitro, which was prevented by maternal treatment with a placenta‐targeted antioxidant (nMitoQ). Moreover, there were no sex differences in the effects of placental factors on fetal cardiomyocyte maturation and growth. Overall, our data suggest that treatment targeted against placental oxidative stress could prevent fetal programming of cardiac diseases via the release of placental factors. Abstract Pregnancy complications associated with placental oxidative stress may impair fetal organ development through the release of placenta‐derived factors into the fetal circulation. We assessed the effect of factors secreted from placentae previously exposed to prenatal hypoxia on fetal cardiomyocyte development and developed a treatment strategy that targets placental oxidative stress by encapsulating the antioxidant MitoQ into nanoparticles (nMitoQ). We used a rat model of prenatal hypoxia (gestational day (GD) 15–21), which was treated with saline or nMitoQ on GD15. On GD21, placentae were harvested, placed in culture, and conditioned medium (containing placenta‐derived factors) was collected after 24 h. This conditioned medium was then added to cultured cardiomyocytes from control dam fetuses. Conditioned medium from prenatally hypoxic placentae increased the percentage of binucleated cardiomyocytes (marker of terminal differentiation) and the size of mononucleated and binucleated cardiomyocytes (sign of hypertrophy), effects that were prevented by nMitoQ treatment. Our data suggest that factors derived from placentae previously exposed to prenatal hypoxia lead to abnormal fetal cardiomyocyte development, and show that treatment against placental oxidative stress may prevent fetal programming of cardiac disease.

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“…When the capacity of antioxidants to scavenge excess ROS are overwhelmed, oxidative stress ensues, exposing the immature cellular defense system of the fetus to high levels of placenta-derived ROS. A role for oxidative stress in developmental programming has been demonstrated by several studies showing that later-life health in offspring born to adverse pregnancy is rescued with antenatal interventions effective in mitigating maternal oxidant load [ 40 , 41 ].…”

Section: Mechanisms: Oxidative Stressmentioning

confidence: 99%

Programming of Vascular Dysfunction in the Intrauterine Milieu of Diabetic Pregnancies

Sallam

Palmgren

Singh

et al. 2018

IJMS

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With the rising global tide of obesity, gestational diabetes mellitus (GDM) burgeoned into one of the most common antenatal disorders worldwide. Macrosomic babies born to diabetic mothers are more likely to develop risk factors for cardiovascular disease (CVD) before they reach adulthood. Rodent studies in offspring born to hyperglycemic pregnancies show vascular dysfunction characterized by impaired nitric oxide (NO)-mediated vasodilation and increased production of contractile prostanoids by cyclooxygenase 2 (COX-2). Vascular dysfunction is a key pathogenic event in the progression of diabetes-related vascular disease, primarily attributable to glucotoxicity. Therefore, glucose-induced vascular injury may stem directly from the hyperglycemic intrauterine environment of GDM pregnancy, as evinced by studies showing endothelial activation and inflammation at birth or in childhood in offspring born to GDM mothers. This review discusses potential mechanisms by which intrauterine hyperglycemia programs dysfunction in the developing vasculature.

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Maternal treatment with a placental-targeted antioxidant (MitoQ) impacts offspring cardiovascular function in a rat model of prenatal hypoxia

Cited by 47 publications

References 34 publications

Prenatal hypoxia impairs cardiac mitochondrial and ventricular function in guinea pig offspring in a sex-related manner

Prenatal hypoxia impairs cardiac mitochondrial and ventricular function in guinea pig offspring in a sex-related manner

Placenta‐targeted treatment in hypoxic dams improves maturation and growth of fetal cardiomyocytes in vitro via the release of placental factors

Programming of Vascular Dysfunction in the Intrauterine Milieu of Diabetic Pregnancies

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