We hypothesized that chronic hypoxia disrupts mitochondrial function via oxidative stress in fetal organs. Pregnant guinea pig sows were exposed to either normoxia or hypoxia (10.5% O2, 14 days) in the presence or absence of the antioxidant, N-acetylcysteine (NAC). Near-term anesthetized fetuses were delivered via hysterotomy, and fetal livers, hearts, lungs, and forebrains harvested. We quantified the effects of chronic hypoxia on cytochrome oxidase (CCO) activity and 2 factors known to regulate CCO activity: malondialdehyde (MDA) and CCO subunit 4 (COX4). Hypoxia increased the MDA levels in fetal liver, heart, and lung with a corresponding reduction in CCO activity, prevented by prenatal NAC. The COX4 expression paralleled CCO activity in fetal liver and lung, but was unaltered in fetal hearts due to hypoxia. Hypoxia reduced the brain COX4 expression despite having no effect on CCO activity. This study identifies the mitochondrion as an important target site in tissue-specific oxidative stress for the induction of fetal hypoxic injury.

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Chronic 17beta-estradiol replacement, at doses producing hormone levels within the physiological range, enhances dilator sensitivity of the coronary microcirculation through enhanced NO production by the endothelium, independent of changes in NO sensitivity of the vascular smooth muscle. Thus, estradiol enhances NO production as a protective mechanism of the coronary microcirculation.

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.

To investigate the effect of chronic hypoxia (HPX) on vasodilation of the fetal heart, we exposed pregnant guinea pigs to room air or 12% O(2) for 4, 7, or 10 days. We excised hearts from anesthetized fetuses (60 +/- 3 days; 65-day gestation = term) and measured changes in both the coronary artery pressure of the isolated constant-flow preparation and endothelial nitric oxide synthase (eNOS) mRNA of fetal ventricles. Dilator responses to cumulative addition (10(-9)-10(-5) M) of acetylcholine and sodium nitroprusside in prostaglandin F(2alpha) (5 x 10(-6) M)-constricted hearts were similar among normoxia (NMX), 4-, 7-, and 10-day HPX (control). Nitro-L-arginine (L-NA, 10(-4)M), a NOS inhibitor, inhibited maximal acetylcholine dilation of hearts exposed to 10-day HPX greater than NMX, 4-, and 7-day HPX. Hypoxia (after 7 and 10 days) increased eNOS mRNA of fetal ventricles compared with NMX and 4-day HPX. 4-Aminopyridine (3 mM), a voltage-dependent K(+)-channel inhibitor, inhibited acetylcholine- but not sodium nitroprusside-induced dilation of NMX and 10-day HPX hearts to a similar magnitude. Glibenclamide (10(-5) M), an ATP-sensitive K(+)-channel inhibitor, had no effect on vasodilation. We conclude that chronic HPX increases the contribution of NO but does not alter K(+)-channel activation in response to acetylcholine-stimulated coronary dilation. Thus increases in NO production via upregulation of eNOS gene expression may be an adaptive response to chronic HPX in the fetal coronary circulation.