Uptake and release of amino acids in the fetal-placental unit in human pregnancies

Holm, Maia Blomhoff; Bastani, Nasser E.; Holme, Ane Moe; Zucknick, Manuela; Jansson, Thomas; Refsum, Helga; Mørkrid, Lars; Blomhoff, Rune; Henriksen, Tore; Michelsen, Trond M.

doi:10.1371/journal.pone.0185760

Cited by 45 publications

(38 citation statements)

References 38 publications

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“…While glycine was also decreased in women with PGDM and GDM during pregnancy, no specific interaction effects were observed. Umbilical glycine during late gestation was previously shown to be produced in the fetal–placental unit and not delivered from the maternal circulation [ 66 , 67 ]. Therefore, diminished glycine in the umbilical cord at birth due to maternal diabetes may be from alterations in fetal or placental production.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

et al. 2020

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Women with diabetes during pregnancy are at increased risk of poor maternal and neonatal outcomes. Despite this, the effects of pre-gestational (PGDM) or gestational diabetes (GDM) on metabolism during pregnancy are not well understood. In this study, we utilized metabolomics to identify serum metabolic changes in women with and without diabetes during pregnancy and the cord blood at birth. We observed elevations in tricarboxylic acid (TCA) cycle intermediates, carbohydrates, ketones, and lipids, and a decrease in amino acids across gestation in all individuals. In early gestation, PGDM had elevations in branched-chain amino acids and sugars compared to controls, whereas GDM had increased lipids and decreased amino acids during pregnancy. In both GDM and PGDM, carbohydrate and amino acid pathways were altered, but in PGDM, hemoglobin A1c and isoleucine were significantly increased compared to GDM. Cord blood from GDM and PGDM newborns had similar increases in carbohydrates and choline metabolism compared to controls, and these alterations were not maternal in origin. Our results revealed that PGDM and GDM have distinct metabolic changes during pregnancy. A better understanding of diabetic metabolism during pregnancy can assist in improved management and development of therapeutics and help mitigate poor outcomes in both the mother and newborn.

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Section: Discussionmentioning

confidence: 99%

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

et al. 2020

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“…Because of the low net water movement between the maternal, placental, and fetal compartments, there may be a change in blood water content between the maternal artery and vein and the umbilical artery and vein. To account for this water shift, we corrected the protein concentrations in the uterine vein and the umbilical artery as described by Holm et al (28).…”

Section: Correction For Water Shift In the Placentamentioning

confidence: 99%

The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4‐vessel sampling

et al. 2018

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We sought to identify proteins secreted by the human placenta into the maternal and fetal circulations. Blood samples from the maternal radial artery and uterine vein and umbilical artery and vein were obtained during cesarean section in 35 healthy women with term pregnancy. Slow off‐rate modified aptamer (SOMA) protein–binding technology was used to quantify 1310 known proteins. The uteroplacental and umbilical venoarterial concentration differences were calculated. Thirty‐four proteins were significantly secreted by the placenta into the maternal circulation, including placental growth factor, growth/differentiation factor 15, and matrix metalloproteinase 12. There were 341 proteins significantly secreted by the placenta into the fetal circulation. Only 7 proteins were secreted into both the fetal and maternal circulations, suggesting a distinct directionality in placental protein release. We examined changes across gestation in the proteins found to be significantly secreted by the placenta into the maternal circulation using serial blood samples from healthy women. Among the 34 proteins secreted into the maternal circulation, 8 changed significantly across gestation. The identified profiles of secreted placental proteins will allow us to identify novel minimally invasive biomarkers for human placental function across gestation and discover previously unknown proteins secreted by the human placenta that regulate maternal physiology and fetal development.—Michelsen, T. M., Henriksen, T., Reinhold, D., Powell, T. L., Jansson, T. The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4‐vessel sampling. FASEB J. 33, 2944–2956 (2019). http://www.fasebj.org

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“…In normal human pregnancy, the concentration of most amino acids, including glutamine, is higher in umbilical venous blood (flowing from placenta to fetus) than in maternal plasma (Holm et al 2017). There are conflicting reports regarding the concentration of glutamine in umbilical venous plasma in FGR compared with normal pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

McIntyre

Hayward

Sibley

et al. 2019

The Journal of Physiology

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Key points Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health. A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus. Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR. Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy. Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. Abstract Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild‐type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin‐like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (Kmf) of 14C‐glutamine and 14C‐glutamate (glutamineKmf and glutamateKmf) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamineKmf and glutamateKmf were higher (P0 versus wild‐type littermates, WTL) at E15.5. At E18.5, glutamineKmf remained elevated whereas glutamateKmf was similar between groups. In summary, we provide evidence that glutamineKmf and glutamateKmf adapt according to placental size in WT mice. The placenta of the growth‐restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.

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Uptake and release of amino acids in the fetal-placental unit in human pregnancies

Cited by 45 publications

References 38 publications

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4‐vessel sampling

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

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