Ascorbate prevents placental oxidative stress and enhances birth weight in hypoxic pregnancy in rats

Abstract

Key points• High-altitude pregnancy is associated with reduced oxygenation and placental complications, which can affect maternal and fetal outcome. However, most high-altitude populations are also impoverished and because maternal undernutrition itself is known to promote placental problems, the extent to which complications during high-altitude pregnancy could be due to maternal oxygen and/or nutrient restriction remains unclear.• The aim of the study was to investigate whether reduced placental oxygenation, independent of maternal undernutrition, increases maternal and placental oxidative stress and whether maternal treatment with vitamin C is protective.• The study shows that hypoxic pregnancy increased maternal circulating and placental molecular indices of oxidative stress.• Maternal vitamin C treatment was protective and increased birth weight.• The study offers insight to mechanism and intervention against the effects of high altitude on pregnancy.Abstract This study isolated the effects of maternal hypoxia independent of changes in maternal nutrition on maternal circulatory and placental molecular indices of oxidative stress and determined whether maternal antioxidant treatment conferred protection. Pregnant rats were subjected to normoxic pregnancy or 13% O 2 chronic hypoxia for most of gestation with and without maternal treatment with vitamin C in the drinking water. Maternal hypoxia with and without vitamin C did not affect maternal food or water intake and led to a significant increase in maternal and fetal haematocrit. At gestational day 20, maternal plasma urate and L-cysteine concentrations, and placental levels of 4-hydroxynonenal and heat shock protein 70 were increased while placental heat shock protein 90 levels were decreased in hypoxic pregnancy. The induction of maternal circulatory and placental molecular indices of oxidative stress in hypoxic pregnancies was prevented by maternal treatment with vitamin C. Maternal hypoxia during pregnancy with or without vitamin C increased placental weight, but not total or compartmental volumes. Maternal treatment with vitamin C increased birth weight in both hypoxic and normoxic pregnancies. The data show that maternal hypoxia independent of maternal undernutrition promotes maternal and placental indices of oxidative stress, effects that can be prevented by maternal treatment with vitamin C in hypoxic pregnancy. While vitamin C may not be the ideal candidate of choice for therapy in pregnant women, and taking into consideration differences in ascorbic acid metabolism between rats and humans, the data do underlie that antioxidant treatment may provide a useful intervention to improve placental function and protect fetal growth in pregnancy complicated by fetal hypoxia.

Vitamin C Prevents Intrauterine Programming of in vivo Cardiovascular Dysfunction in the Rat

“…1 g kg -1 d -1 of vitamin C administration. 63 Although this dose of vitamin C far exceeds that given to pregnant women in all reported clinical trials (1 g per day per woman 64,65 ), the increment from baseline in circulating ascorbate concentrations achieved in dams in the present study was of ca. 70% and, therefore, similar to the increment achieved in pregnant women in the VIP trial following maternal vitamin C administration.…”

“…21 In normoxic pregnancy, maternal food and water intake did not alter significantly between days 6 and 20 of gestation (P>0.05). Furthermore, neither maternal exposure to hypoxia nor vitamin C treatment had any effect on maternal food or water intake or weight gain during the treatment period (P>0.05).…”

“…This degree and duration of maternal hypoxia does not affect maternal food intake, emphasising that in this animal model, any programming effects on cardiovascular function in adult offspring due to hypoxia are independent of alterations in maternal food intake. 11,12, 21 In 1 cohort, animals were subject to euthanasia at day 20 of gestation. Fetal weight and placental weights were recorded for all pregnancies.…”

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

“…Indeed, other gestational insults, such as fetal hypoxia, which also cause IUGR and cardiovascular programming can be overcome by administration of vitamin C (42,43). However, the mechanism is likely different; whereas oxidative stress was attenuated by vitamin C, placental labyrinth zone volume remained unaltered (42,43).…”

The impact of early nutrition on the ageing trajectory

“…As observed in the model of protein restriction and placental insufficiency, evidence of oxidative stress has been demonstrated in this model. This has been reported in the placenta (increased levels of 4-hydroxynonenal and heat-shock protein 70) (103) , and in the heart (increased nitrotyrosine staining and heat-shock protein 70) (102) of rats and in sheep (104) . Furthermore, the administration of the antioxidants allopurinol (104) and vitamin C (105) reversed these phenotypes in sheep.…”