Chronic Hypoxia Impairs Cytochrome Oxidase Activity Via Oxidative Stress in Selected Fetal Guinea Pig Organs

Al-Hasan, Yazan; Evans, LaShauna C.; Pinkas, Gerard A.; Dabkowski, Erinne R.; Stanley, William C.; Thompson, Loren P.

doi:10.1177/1933719112453509

Cited by 39 publications

(53 citation statements)

References 52 publications

(67 reference statements)

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“…In this study, antenatal maternal treatment with a glutathione precursor (NAC) was tested, in order to prevent the long‐lasting vascular effects of FGR. Previous studies using diverse models of FGR in guinea‐pigs have demonstrated that maternal treatment with NAC reduces markers of oxidative stress in different cardiovascular tissues . The present results showed that antenatal treatment with NAC was associated with a normal perinatal and post‐natal growth, and endothelial function.…”

Section: Discussionsupporting

confidence: 70%

Adult vascular dysfunction in foetal growth‐restricted guinea‐pigs is associated with a neonate‐adult switching in Nos3 DNA methylation

et al. 2019

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Aim Foetal growth restriction (FGR) is associated with endothelial dysfunction and cardiovascular diseases in adult subjects. Early vascular remodelling and epigenetic changes occurring on key endothelial genes might precede this altered vascular function. Further, it has been proposed that oxidative stress during development may determine some of these epigenetic modifications. To address this issue, we studied the in vivo and ex vivo vascular function and Nos3 promoter DNA methylation in arteries from eight‐month‐old guinea‐pig born from control, FGR‐treated and FGR‐NAC‐treated pregnancies. Methods Femoral and carotid arteries in vivo vascular function were determined by Doppler, whilst ex vivo vascular function and biomechanical properties were assessed by wire myography. Levels of eNOS mRNA and site‐specific DNA methylation in Nos3 promoter in aorta endothelial cells (AEC) were determined by qPCR and pyrosequencing respectively. Results FGR adult showed an increased femoral vascular resistance (P < .05), stiffness (P < .05) and arterial remodelling (P < .01), along with an impaired NO‐mediated relaxation (P < .001). These effects were prevented by maternal treatment with NAC. Endothelial‐NOS mRNA levels were decreased in FGR adult compared with control and FGR‐NAC (P < .05), associated with increased DNA methylation levels (P < .01). Comparison of Nos3 DNA methylation in AEC showed a differential methylation pattern between foetal and adult guinea‐pigs (P < .05). Conclusion Altogether, these data suggest that adult vascular dysfunction in the FGR does not result from early changes in Nos3 promoter DNA methylation, but from an altered vessel structure established during foetal development.

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Section: Discussionsupporting

confidence: 70%

Adult vascular dysfunction in foetal growth‐restricted guinea‐pigs is associated with a neonate‐adult switching in Nos3 DNA methylation

et al. 2019

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“…; Al‐Hasan et al . ). In contrast, in the present study, NAC treatment reverted the effect of an impaired utero‐placental perfusion on fetal growth restriction not only at the brain level but also by improving fetal weight as well as lower body organs (Table ).…”

Section: Discussionmentioning

confidence: 97%

N‐Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs

Herrera

Cifuentes-Zúñiga

Figueroa

et al. 2016

The Journal of Physiology

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In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetylcysteine (NAC) on fetal endothelial function and endothelial nitric oxide synthase (eNOS) programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, half of the sows receiving NAC in the drinking water (from day 34 until term). Fetal biometry and placental vascular resistance were followed by ultrasound throughout gestation. At term, umbilical arteries and fetal aortae were isolated to assess endothelial function by wire-myography. Primary cultures of endothelial cells (ECs) from fetal aorta, femoral and umbilical arteries were used to determine eNOS mRNA levels by quantitative PCR and analyse DNA methylation in the Nos3 promoter by pyrosequencing. Doppler ultrasound measurements showed that NAC reduced placental vascular resistance in IUGR (P < 0.05) and recovered fetal weight (P < 0.05), increasing fetal-to-placental ratio at term (∼40%) (P < 0.001). In IUGR, NAC treatment restored eNOS-dependent relaxation in aorta and umbilical arteries (P < 0.05), normalizing eNOS mRNA levels in EC fetal and umbilical arteries (P < 0.05). IUGR-derived ECs had a decreased DNA methylation (∼30%) at CpG -170 (from the transcription start site) and this epigenetic signature was absent in NAC-treated fetuses (P < 0.001). These data show that IUGR-ECs have common molecular markers of eNOS programming in umbilical and systemic arteries and this effect is prevented by maternal treatment with antioxidants.

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“…To our knowledge, only three studies have investigated the effects of developmental hypoxia on vertebrate mitochondrial respiration. In mammalian models of prenatal hypoxia, fetuses from pregnant dams exposed to 10% oxygen have lower rates of respiration, mitochondrial efficiency, and enzymatic activities of ETC complexes, and these effects are interpreted as pathological (4, 11). In contrast, the efficiency of ATP production is increased in neuronal mitochondria from chick embryos exposed to 13% oxygen, and this effect is heightened in native highland species (6).…”

Section: Discussionmentioning

confidence: 99%

Developmental plasticity of mitochondrial function in American alligators,Alligator mississippiensis

Galli

Crossley

Elsey

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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The effect of hypoxia on cellular metabolism is well documented in adult vertebrates, but information is entirely lacking for embryonic organisms. The effect of hypoxia on embryonic physiology is particularly interesting, as metabolic responses during development may have life-long consequences, due to developmental plasticity. To this end, we investigated the effects of chronic developmental hypoxia on cardiac mitochondrial function in embryonic and juvenile American alligators (Alligator mississippiensis). Alligator eggs were incubated in 21% or 10% oxygen from 20 to 90% of embryonic development. Embryos were either harvested at 90% development or allowed to hatch and then reared in 21% oxygen for 3 yr. Ventricular mitochondria were isolated from embryonic/juvenile alligator hearts. Mitochondrial respiration and enzymatic activities of electron transport chain complexes were measured with a microrespirometer and spectrophotometer, respectively. Developmental hypoxia induced growth restriction and increased relative heart mass, and this phenotype persisted into juvenile life. Embryonic mitochondrial function was not affected by developmental hypoxia, but at the juvenile life stage, animals from hypoxic incubations had lower levels of Leak respiration and higher respiratory control ratios, which is indicative of enhanced mitochondrial efficiency. Our results suggest developmental hypoxia can have life-long consequences for alligator morphology and metabolic function. Further investigations are necessary to reveal the adaptive significance of the enhanced mitochondrial efficiency in the hypoxic phenotype.

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Chronic Hypoxia Impairs Cytochrome Oxidase Activity Via Oxidative Stress in Selected Fetal Guinea Pig Organs

Cited by 39 publications

References 52 publications

Adult vascular dysfunction in foetal growth‐restricted guinea‐pigs is associated with a neonate‐adult switching in Nos3 DNA methylation

Adult vascular dysfunction in foetal growth‐restricted guinea‐pigs is associated with a neonate‐adult switching in Nos3 DNA methylation

N‐Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs

Developmental plasticity of mitochondrial function in American alligators,Alligator mississippiensis

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