Dataset Information

CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction.

ABSTRACT: Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.

SUBMITTER: Tanner AR

PROVIDER: S-EPMC8348624 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction.

Tanner Amelia R AR Lynch Cameron S CS Kennedy Victoria C VC Ali Asghar A Winger Quinton A QA Rozance Paul J PJ Anthony Russell V RV

International journal of molecular sciences 20210729 15

Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measureme ...[more]

PMID: 34360913

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Project description:Previous research demonstrated that maternal nutrient restriction during mid- to late-gestation influenced net umbilical uptakes of glucose and amino acids in sheep. However, it is unclear how the timing and duration of nutrient restriction during mid- to late-gestation influences net uterine, uteroplacental, and fetal flux of glucose and amino acids. On day 50 of gestation, 41 adolescent ewe lambs carrying singletons were randomly assigned to one of six dietary treatments: 1) 100% of nutrient requirements from days 50 to 90 of gestation (CON; n = 7); 2) 60% of nutrient requirements (RES; n = 7) from days 50 to 90 of gestation; 3) 100% of nutrient requirements from days 50 to 130 of gestation (CON-CON; n = 6); 4) 100% of nutrient requirements from days 50 to 90 of gestation and 60% of nutrient requirements from days 90 to 130 of gestation (CON-RES; n = 7); 5) 60% of nutrient requirements from days 50 to 90 of gestation and 100% of nutrient requirements from days 90 to 130 of gestation (RES-CON; n = 7); or 6) 60% of nutrient requirements from days 50 to 130 of gestation (RES-RES; n = 7). On day 90 (n = 14) and day 130 (n = 27), intraoperative procedures were performed to evaluate uteroplacental blood flows, collect blood samples, and then ewes were euthanized. Net uterine, uteroplacental, and umbilical fluxes of glucose and amino acids were calculated by multiplying blood flow by the arterial-venous concentration difference. Data from days 90 and 130 were analyzed separately using ANOVA in SAS. Maternal nutrient restriction during mid-gestation increased (P = 0.04) net umbilical glucose uptake but, maternal nutrient restriction during late-gestation decreased (P = 0.02) net umbilical glucose uptake. Net umbilical essential amino acid uptake decreased (P = 0.03) with nutrient restriction during mid-gestation; however, net umbilical uptakes of Phe (P = 0.02), Thr (P = 0.05), Met (P = 0.09), and His (P = 0.08) increased or tended to increase after nutrient restriction during late-gestation. These data demonstrate that net umbilical glucose and amino acid uptakes were influenced by the timing of nutrient restriction during mid- to late-gestation. Elevated net umbilical glucose uptake after mid-gestational nutrient restriction was sustained throughout late-gestation, independent of late-gestational feeding level. Long-term adaptations in umbilical glucose uptake may have implications for prenatal and postnatal growth and development of the offspring.

Project description:BackgroundGestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE.ResultsIn silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE.ConclusionsCombining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE.

Dataset Information

CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction.

Publications

CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction.

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