Morphological and molecular changes in the murine placenta exposed to normobaric hypoxia throughout pregnancy

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Abstract
Key points: Exposure of pregnant mice to chronic hypoxia at 13% O2 induces fetal growth restriction but increases placental weight. Sex dimorphism induces differential responses in placental weight to hypoxia. The male placenta is heavier than the female and is associated with less severe fetal growth restriction. Increases in maternal arterial/venous blood spaces and higher protein kinase B (Akt)‐mechanistic target of rapamycin growth signalling could contribute to the heavier hypoxic placenta. Placental endoplasmic reticulum stress is elevated equally in both sexes in response to hypoxia. In comparison, oxidative stress is only apparent in female placentas. Chronic hypoxia induces down‐regulation of placental mitochondrial electron transport chain complexes protein subunits but does not cause intracellular energy depletion. Chronic hypoxia is a common complication of pregnancy, arising through malperfusion of the placenta or pregnancy at high altitude. The present study investigated the effects of hypoxia on the growth of the placenta, which is the organ that interfaces between the mother and her fetus. Mice were housed in an hypoxic environment for the whole of gestation. An atmosphere of 13% oxygen induced fetal growth restriction (1182 ± 9 mg, n = 90 vs. 1044 ± 11 mg, n = 62, P < 0.05) but enhanced placental weight (907 ± 11 mg, n = 90 vs. 998 ± 15 mg, n = 62,P < 0.05). Stereological analyses revealed an increase in the volume of maternal blood spaces in the placenta, consistent with increased flow. At the molecular level, we observed activation of the protein kinase B (Akt)‐mechanistic target of rapamycin growth and proliferation pathway. Chronic hypoxia also triggered mild endoplasmic reticulum stress, a conserved homeostatic response that mediates translational arrest through phosphorylation of eukaryotic initiation factor 2 subunit α. Surprisingly, although subunits of the mitochondrial electron transport chain complexes were reduced at the protein level, there was no evidence of intracellular energy depletion. Finally, we demonstrated sex‐specific placental responses to chronic hypoxia. Placentas from male fetuses were heavier (1082 ± 2 mg, n = 30 vs. 928 ± 2 mg, n = 34, P < 0.05) and less susceptible to hypoxia‐induced oxidative stress than those from females. Their capacity to adapt may explain why male fetuses were significantly less growth restricted at embryonic day 18.5 than their female counterparts. These findings are consistent with the concept that male fetuses are more aggressive with respect to their nutrient demands, which may place them at greater risk of adverse outcomes under limiting conditions.
Funding Information
  • Wellcome Trust (084804/2/08/Z)

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