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. 2021 Sep;9(18):e15033.
doi: 10.14814/phy2.15033.

Uteroplacental nutrient flux and evidence for metabolic reprogramming during sustained hypoxemia

Amanda K Jones  1 , Paul J Rozance  1 , Laura D Brown  1 , Ramón A Lorca  2 , Colleen G Julian  3 , Lorna G Moore  2 , Sean W Limesand  4 , Stephanie R Wesolowski  1
Affiliations

Uteroplacental nutrient flux and evidence for metabolic reprogramming during sustained hypoxemia

Amanda K Jones et al. Physiol Rep. 2021 Sep.

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.

Keywords: fetal; hypoxemia; metabolism; uteroplacental.

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Conflict of interest statement

The authors of this manuscript have no conflict of interest to declare.

Figures

FIGURE 1
FIGURE 1
Effects of sustained hypoxemia on blood flow and oxygen utilization. (a) Relationship between maternal and fetal arterial pO2 measured after 9 days of sustained hypoxemia in CON (white symbols) and HOX (blue symbols) groups. Linear regression was performed, and the Pearson correlation coefficient (r) and significance are indicated. (b) Uterine blood flow (p = 0.361) and umbilical blood flow (p = 0.358) were measured in CON and HOX groups. (c) Uterine (p = 0.643), uteroplacental (p = 0.272), and umbilical (p = 0.376) oxygen utilization (net uptake) rates. Female fetuses are shown with circle and male fetuses with triangle symbols. Means ± SD shown. All results were analyzed by t‐test. Weight specific rates of umbilical blood flow and umbilical oxygen uptake were previously reported (Jones, Rozance, et al., 2019)
FIGURE 2
FIGURE 2
Effect of sustained hypoxemia on net uterine, uteroplacental, and umbilical glucose, lactate, and pyruvate flux. (a) Uterine (p = 0.573), uteroplacental (p = 0.694), and umbilical (p = 0.118) net glucose uptake rates in CON and HOX groups. (b) Relationship between fetal and maternal arterial whole blood glucose concentrations measured with linear regression in CON (white symbols) and HOX (blue symbols) groups. (c) Uterine (p = 0.160), uteroplacental (p = 0.223), and umbilical (p = 0.523) net lactate uptake rates in CON and HOX groups. (d) Uterine (p = 0.256), uteroplacental (p = 0.244), and umbilical (*, p = 0.037) net pyruvate uptake rates in CON and HOX groups. Negative uptake rates indicate net output. (e) Relationship uteroplacental net pyruvate uptake and umbilical net pyruvate uptake rates measured with linear regression in CON (white symbols) and HOX (blue symbols) groups. Female fetuses are shown with circle and male fetuses with triangle symbols. Means ± SD shown. All results were analyzed by t‐test. Pearson correlation coefficients (r) and significance are shown for regression analyses. Weight specific rates of umbilical glucose uptake were previously reported (Jones, Rozance, et al., 2019)
FIGURE 3
FIGURE 3
Effect of sustained hypoxemia on net amino acid flux rates. (a) Uterine net amino acid uptake rates in CON (n = 6) and HOX (n = 6) groups (all p > 0.05). (b) Umbilical net amino acid uptake rates in CON (n = 6) and HOX (n = 6) (#, p < 0.15; *, p < 0.05). (c) Net uteroplacental uptake rates of selected amino acids in CON (n = 6) and HOX (n = 3) (*, p < 0.05). Means ± SD shown. All results were analyzed by t‐test
FIGURE 4
FIGURE 4
Effect of sustained hypoxemia on pathways regulating metabolic reprogramming in the placenta. (a) Relative expression of genes for glucose uptake and utilization, pyruvate oxidation, lactate metabolism, and mitochondrial function were measured in CON (n = 7) and HOX (n = 11) placental tissue (cotyledon). #p < 0.15, *p < 0.05, **p < 0.01. (b) Protein expression was measured by western blotting in CON (n = 7) and HOX (n = 11) placental tissue lysates and quantified. A representative blot of each protein is shown. (c) Protein abundance of phosphorylated (p = 0.294), total (#,p = 0.11), and the ratio of phosphorylated: total PDH (p = 0.517). (d) Protein expression of LDH‐A (**, p = 0.018). (d) PDH activity measured in placental tissue (p = 0.261). (e) LDH activity measured in placental tissue (*, p = 0.043). (f) Thiobarbituric acid‐reactive substances (TBARS) measured in placental tissue (p = 0.672). Means ± SD are shown. Data were analyzed by t‐test
FIGURE 5
FIGURE 5
Effect of sustained hypoxemia on nutrient sensing and signaling pathways in the placenta. Protein abundance was measured by western blotting in CON (n = 7) and HOX (n = 11) placental tissues. (a) Representative western blot image are shown. (b) Protein abundance of phosphorylated (*, p = 0.017), total (p = 0.730), and the ratio of phosphorylated: total AMPK (*, p = 0.013). (c) Protein abundance of phosphorylated (p = 0.991), total (p = 0.975), and the ratio of phosphorylated: total mTOR (p = 0.928). Protein abundance of phosphorylated (p = 0.401), total (p = 0.855), and the ratio of phosphorylated: total S6 (p = 0.786). Protein expression of phosphorylated (p = 0.226), total (p = 0.648), and the ratio of phosphorylated: total 4E‐BP1 (*, p = 0.035). Means ± SD are shown. Data were analyzed by t‐test
FIGURE 6
FIGURE 6
Summary of net uteroplacental nutrient flux rates and relative nutrient allocation. Flux rates for oxygen, glucose, lactate, pyruvate, and selected amino acids are shown in (a) CON and (b) HOX groups. The mean values (absolute rates) for nutrient and oxygen uptake rates across the uterine and umbilical circulation are shown and were used to calculate uteroplacental rates. The solid lines indicate relative magnitude of flux rate and arrows indicate the direction of flux. Dashed arrows indicate a potential fetal conversion of substrates. Relative nutrient allocation as a percentage of total is shown for oxygen, glucose, lactate, and pyruvate with respect to uteroplacental flux (F p) and distribution to the maternal (F M) and fetal (F f) compartments. F in represents total flux of a substrate taken up by the placenta. F out represents total flux of a substrate out of the placenta
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