Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O2) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.
Melatonin participates in circadian, seasonal and reproductive physiology. Melatonin also acts as a potent endogenous antioxidant by scavenging free radicals and upregulating antioxidant pathways. The placenta expresses melatonin receptors and melatonin protects against oxidative damage induced in rat placenta by ischemia-reperfusion. One of the most common complications in pregnancy is a reduction in fetal nutrient delivery, which is known to promote oxidative stress. However, whether melatonin protects placental function and fetal development in undernourished pregnancy is unknown. Here, we investigated the effects of maternal treatment with melatonin on placental efficiency, fetal growth, birth weight and protein expression of placental oxidative stress markers in undernourished pregnancy. On day 15 of pregnancy, rats were divided into control and undernourished pregnancy (35% reduction in food intake), with and without melatonin treatment (5 microg/mL drinking water). On day 20 of gestation, fetal biometry was carried out, the placenta was weighed and subsequently analyzed by Western blot for xanthine oxidase, heat shock protein (HSP) 27 and 70, catalase, manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase 1 (GPx-1). A separate cohort was allowed to deliver to assess effects on birth weight. Maternal undernutrition led to a fall in placental efficiency, disproportionate intrauterine growth retardation and a reduction in birth weight. Maternal treatment with melatonin in undernourished pregnancy improved placental efficiency and restored birth weight, and it increased the expression of placental Mn-SOD and catalase. The data show that in pregnancy complicated by undernutrition, melatonin may improve placental efficiency and birth weight by upregulating placental antioxidant enzymes.
Molecular mechanisms predisposing people to insulin resistance are starting to emerge. Altered insulin signaling for hepatic gluconeogenesis and muscle glucose uptake is thought to play a central role. Development under suboptimal conditions is also known to increase the risk of insulin resistance in adulthood. However, the partial contributions of reduced oxygen vs. nutrient delivery to the fetus, two common adverse conditions in utero, to developmental programming of insulin resistance remain unknown. The aim of this study was to determine the effects of developmental hypoxia or undernutrition on the expression of insulin-signaling proteins in liver and skeletal muscle in adult rat offspring. We show that the expression of hepatic phospho-Akt and muscle Akt2 were significantly reduced in offspring of hypoxic, relative to offspring from normoxic or undernourished, pregnancies. Hepatic Akt-1, Akt-2, and PKCζ protein expression was reduced in offspring from both hypoxic and undernourished pregnancies. Muscle GLUT4 expression was decreased in undernourished, and further decreased in hypoxic, offspring. These findings link prenatal hypoxia to down-regulation of components of hepatic and muscle Akt expression in adult offspring. Akt may represent a pharmaceutical target for clinical intervention against the developmental programming of metabolic disease resulting from prenatal hypoxia.
The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.
In addition to lowering cholesterol, statins increase nitric oxide (NO) bioavailability, improving endothelial function. In the fetus, enhanced NO during acute hypoxia opposes the fetal peripheral vasoconstrictor response, part of the brain-sparing defence. This study tested the hypothesis that treatment with statins depresses the fetal circulatory response to acute hypoxic stress via increasing NO bioavailability. Under anaesthesia, 12 fetal sheep at 118 ± 1 days of gestation (term ca 145 days) were instrumented with vascular catheters and a femoral artery Transonic flow probe for chronic recording. Five days later, all animals were subjected to 30 min of acute hypoxia (fetal arterial partial pressure of O(2) ( ) reduced by ca 50%) before and 24 h after fetal treatment with pravastatin (25 mg i.v.). In half of the fetuses (n = 6), responses to hypoxia post-pravastatin were evaluated during NO synthesis blockade. Fetal exposure to pravastatin did not affect fetal basal cardiovascular function. Fetal was similarly reduced in all acute hypoxia experiments from ca 21 to 10 mmHg. Fetal exposure to pravastatin markedly diminished the fetal femoral vasoconstrictor (5.1 ± 0.9 vs. 2.5 ± 0.5 mmHg (ml min(-1))(-1)) and lactic acidaemic (4.4 ± 0.5 vs. 3.0 ± 0.3 mm) responses to acute hypoxia (both P < 0.05), without affecting plasma catecholamine responses. Post-pravastatin, the circulatory (5.8 ± 1.5 mmHg (ml min(-1))(-1)) and metabolic (3.9 ± 0.3 mm) responses could be restored to control levels during fetal treatment with NO synthase blockade. Pravastatin depresses the fetal cardiovascular and metabolic defences to acute hypoxia via increasing NO bioavailability. The use of statins during pregnancy should be viewed with extreme caution.
Key pointsr Periods of impaired oxygenation or acute hypoxia in the fetus can be common during labour and how the fetus withstands these challenges is of interest.r During hypoxia, the fetus shunts blood flow away from peripheral and towards essential vascular beds: the so called brain-sparing effect.r Part of the peripheral vasoconstriction is driven by reactive oxygen species (ROS) that inactivate nitric oxide (NO), thereby limiting its vasodilator action.r Here, we investigate the source of ROS generation contributing to fetal peripheral vasoconstriction during hypoxia, and show that xanthine oxidase (XO) is fundamentally involved. Fetal exposure to the XO inhibitor allopurinol markedly diminished the peripheral vasoconstriction during hypoxia via NO-dependent mechanisms.r The data increase our understanding of the physiological control of fetal cardiovascular function during stress. The findings are also of significant clinical relevance as allopurinol is being administered to pregnant women in clinical obstetric trials.Abstract Hypoxia is a common challenge to the fetus, promoting a physiological defence to redistribute blood flow towards the brain and away from peripheral circulations. During acute hypoxia, reactive oxygen species (ROS) interact with nitric oxide (NO) to provide an oxidant tone. This contributes to the mechanisms redistributing the fetal cardiac output, although the source of ROS is unknown. Here, we investigated whether ROS derived from xanthine oxidase (XO) contribute to the fetal peripheral vasoconstrictor response to hypoxia via interaction with NO-dependent mechanisms. Pregnant ewes and their fetuses were surgically prepared for long-term recording at 118 days of gestation (term approximately 145 days). After 5 days of recovery, mothers were infused I.V. for 30 min with either vehicle (n = 11), low dose (30 mg kg −1 , n = 5) or high dose (150 mg kg −1 , n = 9) allopurinol, or high dose allopurinol with fetal NO blockade (n = 6). Following allopurinol treatment, fetal hypoxia was induced by reducing maternal inspired O 2 such that fetal basal P aO 2 decreased approximately by 50% for 30 min. Allopurinol inhibited the increase in fetal plasma uric acid and suppressed the fetal femoral vasoconstrictor, glycaemic and lactate acidaemic responses during hypoxia (all P < 0.05), effects that were restored to control levels with fetal NO blockade. The data provide evidence for the activation of fetal XO in vivo during hypoxia and for XO-derived ROS in contributing to the fetal peripheral vasoconstriction, part of the fetal defence to hypoxia. The data are of significance to the understanding of the physiological control of the fetal cardiovascular system during A. D. Kane and J. A. Hansell contributed equally to this study. hypoxic stress. The findings are also of clinical relevance in the context of obstetric trials in which allopurinol is being administered to pregnant women when the fetus shows signs of hypoxic distress.
Key points• There is growing physiological and clinical interest in the role of the enzyme xanthine oxidase in the regulation of fetal cardiovascular function.• The xanthine oxidase inhibitor allopurinol is undergoing human clinical trials in complicated pregnancy to protect the fetal brain from injury by decreasing excessive generation of reactive oxygen species (ROS) and increasing nitric oxide (NO) availability. However, the effects on fetal cardiovascular physiology of xanthine oxidase inhibition are largely unknown.• We have previously reported that the balance between ROS and NO plays an important physiological role in the control of fetal cardiovascular function. Therefore, it seems likely that allopurinol might perturb this balance and alter fetal cardiovascular homeostasis.• Here, we report that maternal allopurinol treatment in late gestation ovine pregnancy has significant in vivo effects on umbilical blood flow and the cardiovascular system of the mother and fetus by altering NO and β 1 -adrenergic mechanisms.• The evidence suggests that xanthine oxidase has an important role in basal cardiovascular function in the fetus during late gestation. Therefore, further research is warranted before safe clinical application of maternal allopurinol during pregnancy in humans.Abstract Virtually nothing is known about the effects on fetal physiology of xanthine oxidase inhibition. This is despite maternal treatment with the xanthine oxidase inhibitor allopurinol being considered in human complicated pregnancy to protect the infant's brain from excessive generation of ROS. We investigated the in vivo effects of maternal treatment with allopurinol on fetal cardiovascular function in ovine pregnancy in late gestation. Under anaesthesia, pregnant ewes and their singleton fetus were instrumented with vascular catheters and flow probes around an umbilical and a fetal femoral artery at 118 ± 1 dGA (days of gestational age; term ca. 145 days). Five days later, mothers were infused I.V. with either vehicle (n = 11) or allopurinol (n = 10). Fetal cardiovascular function was stimulated with increasing bolus doses of phenylephrine (PE) following maternal vehicle or allopurinol. The effects of maternal allopurinol on maternal and fetal cardiovascular function were also investigated following fetal NO blockade (n = 6) or fetal β 1 -adrenergic antagonism (n = 7). Maternal allopurinol led to significant increases in fetal heart rate, umbilical blood flow and umbilical vascular conductance, effects abolished by fetal β 1 -adrenergic antagonism but not by fetal NO blockade. Maternal allopurinol impaired fetal α 1 -adrenergic pressor and femoral vasopressor responses and enhanced the gain of the fetal cardiac baroreflex. These effects of maternal allopurinol were restored to control levels during fetal NO blockade. Maternal treatment with allopurinol induced maternal hypotension, tachycardia and acid-base disturbance. We conclude that maternal treatment with allopurinol alters in vivo maternal, umbilical and fetal vascular functi...
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