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Effects of excess thromboxane A2 on placental development and nutrient transporters in a Mus musculus model of fetal growth restriction.

ABSTRACT: Hypertensive disease of pregnancy (HDP) with placental insufficiency is the most common cause of fetal growth restriction (FGR) in the developed world. Despite the known negative consequences of HDP both to the mother and fetus, little is known about the longitudinal placental changes that occur as HDP progresses in pregnancy. This is because longitudinal sampling of human placentae during each gestation is impossible. Therefore, using a mouse model of thromboxane A2-analog infusion to mimic human HDP in the last trimester, we calculated placental efficiencies based on fetal and placental weights; quantified spongiotrophoblast and labyrinth thicknesses and vascular density within these layers; examined whether hypoxia signaling pathway involving vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR1, VEGFR2) and matrix metalloproteinases (MMPs) contributed to vascular change; and examined nutrient transporter abundance including glucose transporters 1 and 3 (GLUT1, GLUT3), neutral amino acid transporters 1, 2, and 4 (SNAT1, SNAT2, and SNAT4), fatty acid transporters 2 and 4 (FATP2, FATP4), and fatty acid translocase (CD36) from embryonic day 15.5 to 19 in a 20-day C57Bl/6J mouse gestation. We conclude that early-to-mid gestation hypertensive placentae show compensatory mechanisms to preserve fetal growth by increasing placental efficiencies and maintaining abundance of important nutrient transporters. As placental vascular network diminishes over late hypertension, placental efficiency diminishes and fetal growth fails. Neither hypoxia signaling pathway nor MMPs mediated the vascular diminution in this model. Hypertensive placentae surprisingly exhibit a sex-differential expression of nutrient transporters in late gestation despite showing fetal growth failure in both sexes.

SUBMITTER: Gibbins KJ

PROVIDER: S-EPMC6248656 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Effects of excess thromboxane A2 on placental development and nutrient transporters in a Mus musculus model of fetal growth restriction.

Gibbins Karen J KJ Gibson-Corley Katherine N KN Brown Ashley S AS Wieben Matthew M Law Richard C RC Fung Camille M CM

Biology of reproduction 20180501 5

Hypertensive disease of pregnancy (HDP) with placental insufficiency is the most common cause of fetal growth restriction (FGR) in the developed world. Despite the known negative consequences of HDP both to the mother and fetus, little is known about the longitudinal placental changes that occur as HDP progresses in pregnancy. This is because longitudinal sampling of human placentae during each gestation is impossible. Therefore, using a mouse model of thromboxane A2-analog infusion to mimic hum ...[more]

PMID: 29351577

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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.

Project description:Mild gestational hyperglycemia is often associated with fetal overgrowth that can predispose the offspring to metabolic diseases later in life. We hypothesized that unfavorable intrauterine environment may compromise the development of placenta and contribute to fetal overgrowth. Therefore, we developed a rat model and investigated the effects of maternal dysglycemia on fetal growth and placental gene expression. Female rats were treated with single injection of nicotinamide plus streptozotocin (N-STZ) 1-week before mating and were studied at gestational day 21. N-STZ pregnant females displayed impaired glucose tolerance that is associated with a lower insulin secretion. Moderate hyperglycemia induced fetal overgrowth in 40% of newborns, from pregnancies with 10 to 14 pups. The incidence of macrosomia was less than 5% in the N-STZ pregnancies when the litter size exceeds 15 newborns. We found that placental mass and the labyrinthine layer were increased in macrosomic placentas. The expression of genes involved in placental development and nutrient transfer was down regulated in the N-STZ placentas of macrosomic and normosomic pups from pregnancies with 10 to 14 ones. However, we observed that lipoprotein lipase 1 (LPL1) gene expression was significantly increased in the N-STZ placentas of macrosomic pups. In pregnancies with 15 pups or more, the expression of IGFs and glucose transporter genes was also modulated in the control placentas with no additional effect in the N-STZ ones. These data suggest that placental gene expression is modulated by gestational conditions that might disrupt the fetal growth. We described here a new model of maternal glucose intolerance that results in fetal overgrowth. We proposed that over-expression of LPL1 in the placenta may contribute to the increased fetal growth in the N-STZ pregnancies. N-STZ model offers the opportunity to determinate whether these neonatal outcomes may contribute to developmental programming of metabolic diseases in adulthood.

Project description:Litter size is one of the most reliable state-dependent life-history traits that indicate parental investment in polytocous (litter-bearing) mammals. The tendency to optimize litter size typically increases with decreasing availability of resources during the period of parental investment. To determine whether this tactic is also influenced by resource limitations prior to reproduction, we examined the effect of experimental, pre-breeding food restriction on the optimization of parental investment in lactating mice. First, we investigated the optimization of litter size in 65 experimental and 72 control families (mothers and their dependent offspring). Further, we evaluated pre-weaning offspring mortality, and the relationships between maternal and offspring condition (body weight), as well as offspring mortality, in 24 experimental and 19 control families with litter reduction (the death of one or more offspring). Assuming that pre-breeding food restriction would signal unpredictable food availability, we hypothesized that the optimization of parental investment would be more effective in the experimental rather than in the control mice. In comparison to the controls, the experimental mice produced larger litters and had a more selective (size-dependent) offspring mortality and thus lower litter reduction (the proportion of offspring deaths). Selective litter reduction helped the experimental mothers to maintain their own optimum condition, thereby improving the condition and, indirectly, the survival of their remaining offspring. Hence, pre-breeding resource limitations may have facilitated the mice to optimize their inclusive fitness. On the other hand, in the control females, the absence of environmental cues indicating a risky environment led to "maternal optimism" (overemphasizing good conditions at the time of breeding), which resulted in the production of litters of super-optimal size and consequently higher reproductive costs during lactation, including higher offspring mortality. Our study therefore provides the first evidence that pre-breeding food restriction promotes the optimization of parental investment, including offspring number and developmental success.

Dataset Information

Effects of excess thromboxane A2 on placental development and nutrient transporters in a Mus musculus model of fetal growth restriction.

Publications

Effects of excess thromboxane A2 on placental development and nutrient transporters in a Mus musculus model of fetal growth restriction.

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