Abstract
Gestational hypoxemia is often associated with reduced birth weight, yet how hypoxemia controls uteroplacental nutrient metabolism and supply to the fetus is unclear. This study tested the effects of maternal hypoxemia (HOX) between 0.8 and 0.9 gestation on uteroplacental nutrient metabolism and flux to the fetus in pregnant sheep. Despite hypoxemia, uteroplacental and fetal oxygen utilization and net glucose and lactate uptake rates were similar in HOX (n = 11) compared to CON (n = 7) groups. HOX fetuses had increased lactate and pyruvate concentrations and increased net pyruvate output to the utero‐placenta. In the HOX group, uteroplacental flux of alanine to the fetus was decreased, as was glutamate flux from the fetus. HOX fetuses had increased alanine and decreased aspartate, serine, and glutamate concentrations. In HOX placental tissue, we identified hypoxic responses that should increase mitochondrial efficiency (decreased SDHB, increased COX4I2) and increase lactate production from pyruvate (increased LDHA protein and LDH activity, decreased LDHB and MPC2), both resembling metabolic reprogramming, but with evidence for decreased (PFK1, PKM2), rather than increased, glycolysis and AMPK phosphorylation. This supports a fetal‐uteroplacental shuttle during sustained hypoxemia whereby uteroplacental tissues produce lactate as fuel for the fetus using pyruvate released from the fetus, rather than pyruvate produced from glucose in the placenta, given the absence of increased uteroplacental glucose uptake and glycolytic gene activation. Together, these results provide new mechanisms for how hypoxemia, independent of AMPK activation, regulates uteroplacental metabolism and nutrient allocation to the fetus, which allow the fetus to defend its oxidative metabolism and growth.
Highlights
Fetal hypoxemia is a common feature of pregnancies at high altitude and those affected by ischemic placental disease which includes preeclampsia, chronic placental vascular anomalies, and placental insufficiency-induced intrauterine growth restriction (IUGR) (Ananth, 2014; Ananth & Vintzileos, 2008; Giussani, 2016)
Our in vivo uteroplacental flux data provide evidence for a fetal-uteroplacental shuttle during sustained hypoxemia whereby uteroplacental tissues produce lactate as fuel for the fetus using pyruvate released from the fetus, rather than pyruvate produced from glucose in the placenta given the absence of increased uteroplacental glucose uptake and glycolytic gene activation
Our results support the importance of nutrient shuttles between uteroplacental and fetal tissues which provide metabolic advantages for both tissues to maintain oxidative metabolism in the presence of altered proportions of substrates (Jones, Rozance, et al, 2019)
Summary
Fetal hypoxemia is a common feature of pregnancies at high altitude and those affected by ischemic placental disease which includes preeclampsia, chronic placental vascular anomalies, and placental insufficiency-induced intrauterine growth restriction (IUGR) (Ananth, 2014; Ananth & Vintzileos, 2008; Giussani, 2016). This is important because fetuses exposed to hypoxemia across gestation are often born smaller and have an increased risk for developing more severe intrauterine growth restriction (IUGR) (Ducsay et al, 2018; Giussani et al, 2001; Julian et al, 2008; Keyes et al, 2003; Lackman et al, 2001; Moore, 2021; Moore et al, 2011; Soria et al, 2013; Vaughan et al, 2020). The mechanisms underlying the effects of hypoxemia on the placental allocation of these nutrients to the fetus and how the fetus utilizes the available substrates for oxidative metabolism and growth remain largely unknown
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