Conditional Mutation of Hand1 in the Mouse Placenta Disrupts Placental Vascular Development Resulting in Fetal Loss in Both Early and Late Pregnancy.
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SUBMITTER: Courtney JA
PROVIDER: S-EPMC8431056 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Fetal growth restriction is reported to be associated with impaired placental iron transport. Transferrin receptor (TfR) is a major placental iron transporter in humans but has not been studied in sheep. TfR is regulated by both iron and nitric oxide (NO), the molecule produced by endothelial nitric oxide synthase (eNOS). We hypothesized that limited placental development downregulates both placental TfR and eNOS expression, thereby lowering fetal tissue iron.An ovine surgical uterine space restriction (USR) model, combined with multifetal gestation, tested the extremes of uterine and placental adaptation. Blood, tissues, and placentomes from non-space restricted (NSR) singletons were compared with USR fetuses at gestational day (GD) 120 or 130.When expressed proportionate to fetal weight, liver iron content did not differ, whereas renal iron was higher in USR vs. NSR fetuses. Renal TfR protein expression did not differ, but placental TfR expression was lower in USR fetuses at GD130. Placental levels of TfR correlated to eNOS. TfR was localized throughout the placentome, including the hemophagous zone, implicating a role for TfR in ovine placental iron transport.Fetal iron was regulated in an organ-specific manner. In USR fetuses, NO-mediated placental adaptations may prevent the normal upregulation of placental TfR at GD130.
| S-EPMC3678369 | biostudies-literature
Project description:Ex vivo perfusion systems offer a reliable, reproducible method for studying acute physiological responses of an organ to various environmental manipulations. Unlike in vitro culture systems, the cellular organization, compartmentalization and three-dimensional structure of ex vivo-perfused organs are maintained. These particular parameters are crucial for the normal physiological function of the placenta, which supports fetal growth through transplacental exchange, nutritional synthesis and metabolism, growth factor promotion and regulation of both maternally and fetally derived molecules. The perfusion system described here, which can be completed in 4-5 h, allows for integrated, physiological studies of de novo synthesis and metabolism and transport of materials across the live mouse placenta, not only throughout a normal gestation period but also following a variety of individual or combined genetic and environmental perturbations compromising placental function.
| S-EPMC5360402 | biostudies-literature
Project description:BackgroundAdministration of progesterone (P4) to ewes during the first 9 to 12 days of pregnancy accelerates blastocyst development by day 12 of pregnancy, likely due to P4-induced up-regulation of key genes in uterine epithelia responsible for secretion and transport of components of histotroph into the uterine lumen. This study determined if acceleration of blastocyst development induced by exogenous P4 during the pre-implantation period affects fetal-placental development on day 125 of pregnancy. Suffolk ewes (n = 35) were mated to fertile rams and assigned randomly to receive daily intramuscular injections of either corn oil vehicle (CO, n = 18) or 25 mg progesterone in CO (P4, n = 17) for the first 8 days of pregnancy. All ewes were hysterectomized on day 125 of pregnancy and: 1) fetal and placental weights and measurements were recorded; 2) endometrial and placental tissues were analyzed for the expression of candidate mRNAs involved in nutrient transport and arginine metabolism; and 3) maternal plasma, fetal plasma, allantoic fluid, and amniotic fluid were analyzed for amino acids, agmatine, polyamines, glucose, and fructose.ResultsTreatment of ewes with exogenous P4 did not alter fetal or placental growth, but increased amounts of aspartate and arginine in allantoic fluid and amniotic fluid, respectively. Ewes that received exogenous P4 had greater expression of mRNAs for SLC7A1, SLC7A2, SLC2A1, AGMAT, and ODC1 in endometria, as well as SLC1A4, SLC2A5, SLC2A8 and ODC1 in placentomes. In addition, AZIN2 protein was immunolocalized to uterine luminal and glandular epithelia in P4-treated ewes, whereas AZIN2 localized only to uterine luminal epithelia in CO-treated ewes.ConclusionsThis study revealed that exogenous P4 administered in early pregnancy influenced expression of selected genes for nutrient transporters and the expression of a protein involved in polyamine synthesis on day 125 of pregnancy, suggesting a 'programming' effect of P4 on gene expression that affected the composition of nutrients in fetal-placental fluids.
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Project description:Congenital heart disease (CHD) affects nearly 1% of births annually, and CHD pregnancies carry increased risk of developing pathologies of abnormal placentation. We previously reported significant developmental impacts of disrupting Hand1, a gene associated with CHD, expression in placenta trophoblast and endothelial cells in multiple mouse models. In this study, we aimed to build upon this knowledge and characterize the mechanistic impacts of disrupting HAND1 on human placenta trophoblast and vascular endothelial cell gene expression. HAND1 gene expression was silenced in BeWo cells, a choriocarcinoma model of human cytotrophoblasts, (n = 3-9 passages) and isolated human placental microvascular endothelial cells (HPMVEC; n = 3 passages), with HAND1 siRNA for 96 h. Cells were harvested, mRNA isolated and RNA sequencing performed using the Illumina NextSeq 550 platform. Normalization and differential gene expression analyses were conducted using general linear modeling in edgeR packages. Statistical significance was determined using a log2 fold change of >1.0 or < -1.0 and unadjusted p-value ≤0.05. Panther DB was used for overrepresentation analysis, and String DB for protein association network analysis. There was downregulation of 664 genes, and upregulation of 59 genes in BeWo cells with direct HAND1 knockdown. Overrepresentation analysis identified disruption to pathways including cell differentiation, localization, and cell projection organization. In contrast, only seven genes were changed with direct HAND1 knockdown in HPMVECs. Disruption to HAND1 expression significantly alters gene expression profile in trophoblast but not endothelial cells. This data provides further evidence that future studies on genetic perturbations in CHDs should consider the extra-embryonic tissue in addition to the fetal heart.
| S-EPMC9875743 | biostudies-literature
Project description:Obesity and gestational diabetes (GDM) impact fetal growth during pregnancy. Iron is an essential micronutrient needed for energy-intense feto-placental development, but if mis-handled can lead to oxidative stress and ferroptosis (iron-dependent cell death). In a mouse model showing maternal obesity and glucose intolerance, we investigated the association of materno-fetal iron handling and placental ferroptosis, oxidative damage and stress signalling activation with fetal growth. Female mice were fed a standard chow or high fat, high sugar (HFHS) diet during pregnancy and outcomes were measured at day (d)16 or d19 of pregnancy. In HFHS-fed mice, maternal hepcidin was reduced and iron status maintained (tissue iron levels) at both d16 and d19. However, fetal weight, placental iron transfer capacity, iron deposition, TFR1 expression and ERK2-mediated signalling were reduced and oxidative damage-related lipofuscin accumulation in the placenta was increased in HFHS-fed mice. At d19, whilst TFR1 remained decreased, fetal weight was normal and placental weight, iron content and iron transporter genes (Dmt1, Zip14, and Fpn1) were reduced in HFHS-fed mice. Furthermore, there was stress kinase activation (increased phosphorylated p38MAPK, total ERK and JNK) in the placenta from HFHS-fed mice at d19. In summary, a maternal HFHS diet during pregnancy impacts fetal growth trajectory in association with changes in placental iron handling, ferroptosis and stress signalling. Downregulation of placental iron transporters in HFHS mice may protect the fetus from excessive oxidative iron. These findings suggest a role for alterations in placental iron homeostasis in determining perinatal outcomes of pregnancies associated with GDM and/or maternal obesity.
| S-EPMC10963579 | biostudies-literature
Project description:Fetal growth restriction (FGR) occurs when the fetus does not reach its genetically programmed intrauterine potential for growth and affects ~5‑10% of pregnancies. This condition is one of the leading causes of perinatal mortality and morbidity associated with obstetric and neonatal complications. Placental dysfunction in FGR causes an impairment in the transfer of nutrients and oxygen from the mother to the developing fetus. Maternal adaptations to placental insufficiency may also play a role in the pathophysiology of FGR. The present study aimed to compare the proteome of the placentas of 18 women with the physiological course of pregnancy and eutrophic fetus [estimated fetal weight (EFW) >10th percentile; control group] and 18 women with late FGR (EFW <10th percentile) diagnosed after 32 weeks of pregnancy, according to the Delphi consensus (study group). The U. Mann‑Whitney test was used to compare two independent groups. The R. Spearman correlation coefficient significance test was used to assess the existence of a relationship between the analyzed measurable parameters. P<0.05 was considered to indicate a statistically significant difference. The tests showed the presence of 356 different proteins which were responsible for the regulation of gene transcription control, inhibiting the activity of proteolytic enzymes, regulation of trophoblast proliferation and angiogenesis and inflammatory response. In the FGR placental proteome, other detected proteins were mostly involved in response to oxidative stress, cellular oxidation and detoxication, apoptosis, hemostatic and catabolic processes, energy transduction protein interactions, cell proliferation, differentiation and intracellular signaling. The present study used chromatographic mass‑spectrometry to compare the placental proteome profiles in pregnancies complicated by late‑onset FGR and normal pregnancy. Comparative analysis of proteomes from normal and FGR placentas showed significant differences. Further research is needed to clarify maternal and fetal adaptations to FGR.
| S-EPMC9608316 | biostudies-literature
Project description:ObjectiveCurrently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement.MethodsFollowing third trimester presentation with reduced fetal movement (N = 100), placental structure ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium).ResultsPlacentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area (all p<0.0001) compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10-12) vessels/mm2 vs. normal outcome 13 (12-15), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19-50) nM vs. 12 (6-24), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11-50) vs. 55 (24-102) mIU/mg, p = 0.007) and human placental lactogen (11 (6-14) vs. 27 (9-50) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13-29) vs. 5 (2-15) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue.ConclusionThese data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction.
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Project description:During pregnancy, maternal vitamin D insufficiency could increase the risk of preeclampsia. Aim of the study was to evaluate the relationship between vitamin D status and the occurrence of placenta-mediated complications (PMCs) in a population at high risk. A prospective multicenter cohort study of 200 pregnant patients was conducted. The vitamin D level of patients with placenta-mediated complications was lower at 32 weeks compared to uncomplicated pregnancies (P = 0.001). At 32 weeks, the risk of occurrence of PMCs was five times higher in patients with vitamin D deficiency (RR: 5.14 95% CI (1.50-17.55)) compared to patients with normal vitamin D levels. There was a strong, inverse relationship between serum 25(OH)D levels at 32 weeks and the subsequent risk of PMCs (P = 0.001). At 32 weeks, the vitamin D level of patients with late-onset PMCs was lower than the one of patients with early-onset PMCs and of patients without PMCs (P < 0.0001). These results suggest a role of vitamin D in the maintenance of placental performance and therefore in the prevention of the onset of late PMC.
| S-EPMC8528848 | biostudies-literature
Project description:Key pointsFetal glucagon concentrations are elevated in the setting of placental insufficiency, hypoxia and elevated stress hormones. Chronically elevated glucagon concentrations in the adult result in profound decreases in amino acid concentrations and lean body mass. Experimental elevation of fetal glucagon concentrations in a late-gestation pregnant sheep results in lower fetal amino acid concentrations, lower protein accretion and lower fetal weight, in addition to decreased placental function. This study demonstrates a negative effect of glucagon on fetal protein accretion and growth, and also provides the first example of a fetal hormone that negatively regulates placental nutrient transport and blood flow.AbstractFetal glucagon concentrations are elevated in the setting of placental insufficiency and fetal stress. Postnatal studies have demonstrated the importance of glucagon in amino acid metabolism, and limited fetal studies have suggested that glucagon inhibits umbilical uptake of certain amino acids. We hypothesized that chronic fetal hyperglucagonaemia would decrease amino acid transfer and increase amino acid oxidation by the fetus. Late gestation singleton fetal sheep received a direct intravenous infusion of glucagon (GCG; 5 or 50 ng/kg/min; n = 7 and 5, respectively) or a vehicle control (n = 10) for 8-10 days. Fetal and maternal nutrient concentrations, uterine and umbilical blood flows, fetal leucine flux, nutrient uptake rates, placental secretion of chorionic somatomammotropin (CSH), and targeted placental gene expression were measured. GCG fetuses had 13% lower fetal weight compared to controls (P = 0.0239) and >28% lower concentrations of 16 out of 21 amino acids (P < 0.02). Additionally, protein synthesis was 49% lower (P = 0.0005), and protein accretion was 92% lower in GCG fetuses (P = 0.0006). Uterine blood flow was 33% lower in ewes with GCG fetuses (P = 0.0154), while umbilical blood flow was similar. Fetal hyperglucagonaemia lowered uterine uptake of 10 amino acids by >48% (P < 0.05) and umbilical uptake of seven amino acids by >29% (P < 0.04). Placental secretion of CSH into maternal circulation was reduced by 80% compared to controls (P = 0.0080). This study demonstrates a negative effect of glucagon on fetal protein accretion and growth. It also demonstrates that glucagon, a hormone of fetal origin, negatively regulates maternal placental nutrient transport function, placental CSH production and uterine blood flow.
| S-EPMC8249343 | biostudies-literature
Project description:To date, mother-to-fetus transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19) pandemic, remains controversial. Although placental COVID-19 infection has been documented in some cases during the second- and third-trimesters, no reports are available for the first trimester of pregnancy, and no SARS-CoV-2 protein has been found in fetal tissues. We studied the placenta and fetal organs from an early pregnancy miscarriage in a COVID-19 maternal infection by immunohistochemical, reverse transcription quantitative real-time polymerase chain reaction, immunofluorescence, and electron microscopy methods. SARS-CoV-2 nucleocapsid protein, viral RNA, and particles consistent with coronavirus were found in the placenta and fetal tissues, accompanied by RNA replication revealed by double-stranded RNA (dsRNA) positive immunostain. Prominent damage of the placenta and fetal organs were associated with a hyperinflammatory process identified by histological examination and immunohistochemistry. The findings provided in this study document that congenital SARS-CoV-2 infection is possible during the first trimester of pregnancy and that fetal organs, such as lung and kidney, are targets for coronavirus. The infection and multi-organic fetal inflammation produced by SARS-CoV-2 during early pregnancy should alert clinicians in the assessment and management of pregnant women for possible fetal consequences and adverse perinatal outcomes.
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