Placental Structure Research Articles

1112HAND1 knockdown disrupts trophoblast but not placental endothelial global gene expression

We previously reported disrupted placental structure, and vascular changes in placentas from fetuses with Congenital Heart Defects. Signaling between trophoblast and villous endothelium is proposed for proper placental development and function. We hypothesize that disruption of genes associated with CHD within the trophoblast impacts fetal endothelium and results in dysregulated placental vasculature in CHD fetuses. A model of human cytotrophoblast, BeWo choriocarcinoma cells and isolated human placental microvascular endothelial cells (HPMVEC) were treated for 48 hrs with HAND1 siRNA/lipofectamine. Additionally, control HPMVECs were exposed to conditioned BeWo media (+/- HAND1) for 48 hrs. Cells were harvested and total RNA isolated. RNA was sequenced on an Illumina NextSeq 550 platform (single end reads 85bp, read depth 25M). The Galaxy Bioinformatic Platform was used for quality control, alignment (Bowtie2) and generation of read counts (Feature Counts). Normalization and differential gene expression analyses were conducted using general linear modeling in edgeR package from Bioconductor. Significance was determined using a fold change cut off of >1.5 and raw p<0.05. Overrepresentation analysis was performed using Panther DB for Reactome pathways and GO terms Direct HAND1 knockdown in the BeWo choriocarcinoma cell line caused downregulation of 632 genes, and upregulation of 102 genes. Overrepresentation analysis identified disruption to pathways including cell differentiation, neurogenesis, localization, and cell projection organization. In contrast, direct HAND1 knockdown in HPMVECs resulted in minimal disruption to global gene expression with differential expression in just 18 genes. Indirect HAND1 disruption did not alter HPMVEC gene expression. Disruption to HAND1 expression significantly alters gene expression profile in trophoblast but not HPMVEC, either directly or indirectly. Disruption to the structure and vasculature of the placenta in cases of CHD is likely primarily due to abnormal trophoblast development.

Syncytins expressed in human placental trophoblast

Three versions of syncytiotrophoblast exist in the human placenta: an invasive type associated with the implanting conceptus, non-invasive villous type of definitive placenta, and placental bed giant cells. Syncytins are encoded by modified env genes of endogenous retroviruses (ERV), but how they contribute functionally to placental syncytial structures is unclear. A minimum of eight genes (ERVW1, ERVFRD-1, ERVV-1, ERVV-2, ERVH48-1, ERVMER34-1, ERV3-1, & ERVK13-1) encoding syncytin family members are expressed in human trophoblast, the majority from implantation to term. ERVW1 (Syncytin 1) and ERVFRD-1 (Syncytin 2) are considered the major fusogens, but, when the expression of their genes is analyzed by single cell RNAseq in first trimester placenta, their transcripts are distinctly patterned and also differ from those of their proposed binding partners, SLC1A5 and MFSD2A, respectively. ERVRH48-1 (suppressyn or SUPYN) and ERVMER34-1 are probable negative regulators of fusion and co-expressed, primarily in cytotrophoblast. The remaining genes and their products have been little studied. Syncytin expression is a feature of placental development in almost all eutherian mammals studied, in at least one marsupial, and in viviparous lizards, which lack the trophoblast lineage. Their expression has been inferred to be essential for pregnancy success in the mouse. All the main human ERV genes arose following independent retroviral insertion events, none of which trace back to the divergence of eutherians and metatherians (marsupials). While syncytins may be crucial for placental development, it seems unlikely that they helped orchestrate the divergence of eutherians and marsupials.

Effects of maternal nutrient restriction during the periconceptional period on placental development in the mouse.

Maternal undernutrition has detrimental effects on fetal development and adult health. Total caloric restriction during early pregnancy followed by adequate nutrition for the remainder of gestation, is particularly linked to cardiovascular and metabolic disease risks during adulthood. The placenta is responsible for transport of nutrients from the maternal to fetal circulation, and the efficiency with which it does so can be adjusted to the maternal nutrient supply. There is evidence that placental adaptations to nutrient restriction in early pregnancy may be retained even when adequate nutrition is restored later in pregnancy, leading to a potential mismatch between placental efficiency and maternal nutrient supplies. However, in the mouse, 50% caloric restriction from days 1.5–11.5 of gestation, while temporarily altering placental structure and gene expression, had no significant effect on day 18.5. The periconceptional period, during which oocyte maturation, fertilization, and preimplantation development occur may be especially critical in creating lasting impact on the placenta. Here, mice were subjected to 50% caloric restriction from 3 weeks prior to pregnancy through d11.5, and then placental structure, the expression of key nutrient transporters, and global DNA methylation levels were examined at gestation d18.5. Prior exposure to caloric restriction increased maternal blood space area, but decreased expression of the key System A amino acid transporter Slc38a4 at d18.5. Neither placental and fetal weights, nor placental DNA methylation levels were affected. Thus, total caloric restriction beginning in the periconceptional period does have a lasting impact on placental development in the mouse, but without changing placental efficiency.

Activation of the ERK1/2 signaling pathway enhances proliferation and apoptosis of trophoblast in preeclampsia rats.

The aim of this study was to investigate the influences of the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway on preeclampsia rats as well as the proliferation and apoptosis of trophoblasts. A proper number of conceived rats were applied to prepare the preeclampsia model (group P). Meanwhile, others were enrolled as control group (group C). The differences in placental structure between the two groups were compared via hematoxylin-eosin (HE) staining. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were compared between the two groups as well. In addition, T25 cell lines were divided into three groups, including Control group, hypoxia/reoxygenation (H/R) group and H/R + Staurosporine group (an activator of the ERK1/2 signaling pathway). The protein expression of phosphorylated (p)-ERK1/2 in the aforementioned model groups and cells was detected through Western blotting. Cell apoptosis rate was determined by a flow cytometer. Moreover, methyl thiazolyl tetrazolium was utilized to measure the proliferative capacity of trophoblasts in the three groups. Transwell chamber assay was adopted to count the transmembrane cells. The cells in group P were arranged disorderly. Group P had remarkably lower SOD activity but higher MDA content than group C (p<0.05). The protein expression levels of ERK1/2 and p-ERK1/2 in the placenta of group C were evidently higher than those of group P (p<0.05). Besides, the protein expression levels of ERK1/2 and p-ERK1/2 were markedly up-regulated in Control group when compared with H/R + Staurosporine group, with the lowest in H/R group (p<0.05). The proliferative capacity of cells was gradually enhanced in the three groups with the increase of culture time. Cell proliferation was the strongest in Control group, followed by H/R + Staurosporine group and H/R group (p<0.05). The apoptosis and death rates of cells were the highest in H/R group, followed by H/R + Staurosporine group and Control group (p<0.05). However, the number of transmembrane cells was the largest in Control group, followed by H/R + Staurosporine group and H/R group (p<0.05). The ERK1/2 signaling pathway is associated with preeclampsia in rats, whose activation can enhance cell proliferation and weaken cell apoptosis.

Особенности васкулогенеза и ангиогенеза в плаценте на фоне химиотерапии

Aim: to study placental vasculogenesis and angiogenesis in women receiving chemotherapy. Patients and Methods: placental structure was examined in 57 pregnant women aged 22–38 years who were subdivided into 3 groups, i.e., women with malignancies receiving or not receiving chemotherapy and healthy controls. The slices of the central part of placentas collected after childbirth were examined. Immunohistochemistry (IHC) was performed after standard histology. IHC intensity was assessed for CD31 and CD34. In addition to IHC intensity, the number of positive cells per field of view was calculated for VEGF, VEGFR1, and VEGFR2. Mean counts of positive cells separately for epithelial and stromal cells were calculated for eNOS. Results: in the control group, the maturity of the placental villous tree matched the gestational age. Meanwhile, in 100% of pregnant women with malignancies receiving chemotherapy and in 46.8% of pregnant women with malignancies not receiving chemotherapy, the maturity of the placental villous tree was 2–4 weeks behind the gestational age. IHC revealed no significant differences in the placental concentrations of CD31, CD39, eNOS, VEGF, VEGFR1, and VEGFR2 between women with malignancies not receiving chemotherapy and the controls. In women receiving chemotherapy, IHC intensity and the number of positive cells were twice as high as in the control group. The activity of VEGFR1 and VEGFR2 was 11 times higher and 1.4 times higher, respectively, than in the control group. The mean number of cells expressing VEGFR1 and VEGFR2 per field of view increased by 1.5 times and 1.7 times, respectively. In addition, 1.6-fold reduction in CD31 level and 1.3-fold reduction in CD34 level as well as 1.4-fold increase in epithelial еNOS level and 1.3-fold increase in stromal eNOS level were revealed. Conclusions: our findings on IHC distribution of the expression of VEGF and its recep-tors in the placental tissue of pregnant women undergoing cytostatic chemotherapy in part illus-trate the processes of the compensation and impaired functioning of the mother-placentafetus system in pre-placental hypoxia. KEYWORDS: angiogenesis, vasculogenesis, vascular growth factor, chemotherapy, hypoxia, placental insufficiency. FOR CITATION: Yu.E. Dobrokhotova, Borovkova E.I., Arutyunyan A.M. et al. Placental vasculogenesis and angiogenesis in women undergoing chemotherapy. Russian Journal of Woman and Child Health. 2021;4(1):23–30. DOI: 10.32364/2618-8430-2021-4-1-23-30.

HGF/c-Met signaling regulates early differentiation of placental trophoblast cells.

Depletion of hepatocyte growth factor (HGF) or mesenchymal-epithelial transition factor (c-Met) in mice leads to fetal lethality and placental maldevelopment. However, the dynamic change pattern of HGF/c-Met signaling during placental development and its involvement in the early differentiation of trophoblasts remain to be elucidated. In this study, using in situ hybridization assay, we elaborately demonstrated the spatial-temporal expression of Hgf and c-Met in mouse placenta from E5.5, the very early stage after embryonic implantation, to E12.5, when the placental structure is well developed. The concentration of the soluble form of c-Met (sMet) in maternal circulation peaked at E10.5. By utilizing the induced differentiation model of mouse trophoblast stem cells (mTSCs), we found that HGF significantly promoted mTSC differentiation into syncytiotrophoblasts (STBs) and invasive parietal trophoblast giant cells (PTGCs). Interestingly, sMet efficiently reversed the effect of HGF on mTSC differentiation. These findings indicate that HGF/c-Met signaling participates in regulating placental trophoblast cell fate at the early differentiation stage and that sMet acts as an endogenous antagonist in this aspect.

Плацента как орган-мишень материнского ожирения

Maternal obesity is associated with pregnancy complications and increases the risk of obesity, diabetes, and cardiovascular diseases in children later in life. The risk of adverse perinatal outcomes in maternal obesity is associated with changes in placental function and morphological structure, including decidual arteriopathy and placental infarction, increased placental disc mass (&gt;90th percentile) and chronic inflammation of villi with a decrease in their number. Maternal obesity is associated with placental hypoxia, intense angiogenesis, and increased levels of glucose and amino acid transporter transcripts, which can cause fetal metabolic disorders. It was found that maternal obesity more often leads to inflammatory changes in the placenta of female fetuses. The review describes the main adipokines operating in the maternal-placental-fetal system: leptin, adiponectin, chemerin, visfatin, resistin, and apelin. Conclusion. The analysis of the literature enabled to identify the main statements characterizing the placenta as a target organ and an organ that changes fetal metabolism in case of maternal obesity. This reveals the prospects for therapeutic intervention since timely initiated dietary correction of obesity can improve the course and prognosis of pregnancy and reduce the risk of adverse effects of intrauterine factors on the fetus. Key words: adipokines, maternal obesity, fetal metabolic disorders, perinatal outcomes

Preconception preparation for pregnancy

Background. Experience in high-risk obstetrics shows that a significant part of the determining factors affects the woman and the fetus before the first visit to the doctor. Improving a woman’s health before conception can improve her reproductive performance and reduce financial costs spent on obstetric medical aid.&#x0D; Objective. Describe the key concepts of preconception training.&#x0D; Materials and methods. Analysis of literature sources on this topic; own study involving 42 pregnant women (22 women with systemic lupus erythematosus (SLE), 20 women with congenital heart disease (CHD) and hypertensive complications of previous pregnancies), who were divided into two groups. Group 1 received routine drugs and L-arginine (Tivortin, “Yuria-Pharm”) in doses recommended for cardiac patients, and group 2 – only routine drugs.&#x0D; Results and discussion. The components of preconception programs include the individual responsibility of women throughout life, awareness of women, preventive visits, interventions on identified risks, pre-pregnancy examinations and pregnancy supervision, health insurance for low-income women, health programs and strategies, medical research, and the improvement of monitoring. Target groups of preconception include women with unfavorable obstetric history (premature birth, cessation of fetal development, cesarean section, stillbirth, multiple miscarriages, birth of children with birth defects, hypertensive complications of pregnancy) and chronic diseases (type 1 diabetes mellitus, SLE, antiphospholipid syndrome, severe cardiovascular pathology, arterial hypertension, pulmonary hypertension). An important role in the management of pregnant women belongs to the prevention of preeclampsia (PE). Administration of acetylsalicylic acid reduces the likelihood of PE by 10 % in low-risk pregnant women and by 25 % in high-risk pregnant women, but the drug should be started during gestation. The use of calcium (1000 mg) reduces the risk of PE in high-risk pregnant women by 37 %. Preconception preparation is especially important, because some processes, such as the implantation of placental structures, begin and end before a woman learns she is pregnant. Remodeling of the spiral arteries also begins in the early stages of pregnancy, so its correction after the confirmation of pregnancy is less effective than prevention before it occurs. E.E. Camarena Pulido et al. (2016) studied the role of L-arginine (5 tablets of 600 mg per day from the 20th week of gestation before delivery) in the prevention of PE in high-risk women. In the L-arginine group significantly fewer cases of PE (3/49 vs. 11/47 in the placebo group; p=0.01) and a lower incidence of preterm birth were detected. In the another study, pregnant women with chronic hypertension received oral L-arginine or placebo. In the arginine group, there was a lower need for antihypertensive drugs, as well as lower frequency of births before 34 weeks, PE and neonatal complications (Neri I. et al., 2010). In the own study, favorable obstetric results of Tivortin were found. The percentage of births at &gt;37 weeks in the Tivortin group among women with SLE was 90.9 %, and in the group of standard therapy – 50 % (p&lt;0.01), among women with CHD – 90 % and 75 % respectively; p&lt;0.05). No newborns with an Apgar score of &lt;7 were found in the Tivortin group. In the comparison group their number was 27.7 %. Laboratory studies have shown that there is a significant increase in endothelial progenitor cells in the Tivortin group.&#x0D; Conclusions. 1. Preconception preparation of pregnant women is a multifaceted set of measures. 2. A significant number of physiological and pathological processes occur in the early stages of pregnancy, so they can be influenced only in the preconception period. 3. The use of L-arginine during gestation reduces the risk of PE, premature birth and other complications in all women and especially in women with hypertension.

Effects of In Utero Exposure to Perfluorooctane Sulfonate on Placental Functions.

Perfluorooctane sulfonate (PFOS) is a metabolic-disrupting chemical. There is a strong association between maternal and cord blood PFOS concentrations, affecting metabolism in early life. However, the underlying effects have not been fully elucidated. In this study, using the maternal-fetal model, we investigated the impact of gestational PFOS exposure on the placental structure and nutrient transport. Pregnant mice were oral gavaged with PFOS (1 or 3 μg PFOS/g body weight) from gestational day (GD) 4.5 until GD 17.5. Our data showed a significant reduction in fetal body weight at high dose exposure. There were no noticeable changes in placental weights and the relative areas of junctional and labyrinth zones among the control and exposed groups. However, a placental nutrient transport assay showed a significant reduction in maternal-fetal transport of the glucose and amino acid analogues. Western blot analysis showed a significant decrease in the expression levels of placental SNAT4 upon PFOS exposure. Moreover, in the high-dose exposed group, placenta and fetal livers were found to have significantly higher corticosterone levels, a negative regulator of fetal growth. The perturbation in the placental transport function and corticosterone levels accounted for the PFOS-induced reduction of fetal body weights.

The potential role of the E SRRG pathway in placental dysfunction.

Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions. Here we review evidence that supports a role for estrogen related receptor-gamma (ESRRG) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ESRRG is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA (miRNA) or other potential upstream regulators of ESRRG negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, miRNAs regulate ESRRG expression in human trophoblast. Thus, if ESRRG is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta. This review explores altered expression of ESRRG and upstream regulation of ESRRG-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ESRRG pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.

Pregnant alpha-1-microglobulin (A1M) knockout mice exhibit features of kidney and placental damage, hemodynamic changes and intrauterine growth restriction

Alpha-1-microglobulin (A1M) is an antioxidant previously shown to be elevated in maternal blood during pregnancies complicated by preeclampsia and suggested to be important in the endogenous defense against oxidative stress. A knockout mouse model of A1M (A1Mko) was used in the present study to assess the importance of A1M during pregnancy in relation to the kidney, heart and placenta function. Systolic blood pressure (SBP) and heart rate (HR) were determined before and throughout gestation. The morphology of the organs was assessed by both light and electron microscopy. Gene expression profiles relating to vascular tone and oxidative stress were analyzed using RT-qPCR with validation of selected gene expression relating to vascular tone and oxidative stress response. Pregnant age-matched wild type mice were used as controls. In the A1Mko mice there was a significantly higher SBP before pregnancy that during pregnancy was significantly reduced compared to the control. In addition, the HR was higher both before and during pregnancy compared to the controls. Renal morphological abnormalities were more frequent in the A1Mko mice, and the gene expression profiles in the kidney and the heart showed downregulation of transcripts associated with vasodilation. Simultaneously, an upregulation of vasoconstrictors, blood pressure regulators, and genes for osmotic stress response, ion transport and reactive oxygen species (ROS) metabolism occurred. Fetal weight was lower in the A1Mko mice at E17.5. The vessels in the labyrinth zone of the placentas and the endoplasmic reticulum in the spongiotrophoblasts were collapsed. The gene profiles in the placenta showed downregulation of antioxidants, ROS metabolism and oxidative stress response genes. In conclusion, intact A1M expression is necessary for the maintenance of normal kidney, heart as well as placental structure and function for a normal pregnancy adaptation.

Abstract 17061: Impact of Maternal Anxiety on In Vivo Placental Development in Fetuses With Congenital Heart Disease

Introduction: Studies have shown that maternal stress and anxiety during pregnancy have been associated with a higher incidence of preterm birth and low birth weight. However, the relationship between prenatal maternal mental distress and placental development in fetuses with congenital heart disease (CHD) is unknown. Hypothesis: We tested the hypothesis that elevated maternal anxiety is associated with altered placental morphology in fetuses with CHD. Methods: A total of 141 pregnant women were recruited prospectively (control: 91; two-ventricle/2V CHD: 29; single-ventricle/SV CHD: 21), in which 228 fetal MR scans were performed (gestational age: 31.8±4.5 weeks). Single shot fast spin echo T2-weighted images were acquired on a 1.5 Tesla GE MRI scanner. Placenta tissue was manually segmented, and slice-to-volume registration was used for motion correction and 3D reconstruction. Six placental features were calculated: volume, thickness, elongation, surface area, mean diameter, and umbilical cord centricity. We completed the Spielberger State (SSAI) and Trait (SSAI) Anxiety Inventory at each study visit. Linear mixed models were utilized to analyze the placental features predicted by maternal anxiety. Results: Placental volume, surface area, and mean diameter were decreased with elevated SSAI in 2V CHD fetuses, while volume and cord centricity were increased with higher SSAI in SV CHD fetuses. Lower cord centricity was associated with elevated STAI in 2V CHD fetuses, and elongation was positively associated with STAI in SV CHD fetuses. There were no associations between anxiety measures and placental features in control fetuses. Conclusions: We report for the first time that elevated prenatal maternal anxiety is associated with altered in vivo placental structures in pregnancies complicated by fetal CHD. Our data suggest that disturbances in placental structure vary based on the type of fetal CHD (SV vs. 2V) in the setting of elevated prenatal maternal anxiety.

Особливості плацентарних структур у жінок з передчасними пологами

The objective: study of histochemical, morpho-functional features of placentas in premterm birth at different gestational ages. Materials and methods. We examined 172 pregnant women, who were hospitalized and gave birth in the Perinatal Center of Kyiv during 2016–2018 years at 24–33 weeks of gestation. The control group included 40 women with a physiological course of singleton pregnancy at 38–41 weeks of gestation. Patients of the experimental group were divided into three subgroups: the first consisted of 46 pregnant women at 22–27 weeks of gestation, the second one – of 44 pregnant women at 28–33 weeks, the third one – of 42 pregnant women at 34–37 weeks. Clinical and statistical analysis of exchange cards of pregnant women (form 113/y) and birth histories (form 096/0) of mothers of all groups was performed. For morphofunctional assessment of placenta in the study histological (staining with hematoxylin-eosin after Van-Gizon) and immunohistochemical (indirect streptavidin-peroxidase – for detection of progesterone receptor’s expression level) methods were used. Results. No significant age difference was found between the study groups. More than 66.5% of patients had a second pregnancy. Obstetric and gynecological history of women are burdened in most cases by the following conditions: previous premature birth, miscarriage, inflammatory diseases, extragenital pathology (diseases of the urinary and endocrine systems). When analyzing the results of histological examination of the placenta in patients whose pregnancies resulted in childbirth at 22–27 weeks, inflammatory changes in the placenta were found in 84.8%, and in women in labor at 28–33 weeks – only 56.8%. At 34–37 weeks of gestation, the percentage of inflammatory changes in placental structures do not have a significant difference with the control group (30.9% and 27.5%, respectively; p≤0.05). With gestational age increase the percentage of involutive-dystrophic changes in the placenta decreases, the number of circulatory disorders increases, and accelerated chorionic maturation is observed. Analysis of the data of monoclonal antibodies’ to progesterone receptors expression in the structures of the placenta depending on gestational age revealed the greatest expression in decidual membranes (55%) in very early preterm birth, which had a significant difference with the control group (14%), (p&lt;0.05) . In women of group II, the level of expression of progesterone receptors was reduced (30%), but had no significant difference with group III of the studied placentas (26%), (p&gt;0.05). Immunohistochemical examination of the progesterone receptors (PR) shows a reaction in the epithelium and stem cells of the stroma, intermediate and terminal villi; in amniotic membranes and extravillous cytotrophoblast; in the vascular endothelium. Conclusion. In very early preterm birth, inflammatory changes and significant expression activity of progesterone receptors predominate in placental structures. During childbirth at 33–37 weeks of gestation the most common disorders are maturation of the villous chorion, combined with circulatory and involutive-dystrophic changes. Keywords: preterm labor, placenta, histological changes, immunohistochemistry, progesterone receptors.

Characterization of Placental Microvascular Architecture by MV-Flow Imaging in Normal and Fetal Growth-Restricted Pregnancies.

To observe the microvascular architecture in the placental bed and explore the feasibility and clinical utility of MV-Flow imaging (Samsung Medison Co, Ltd, Seoul, Korea) during normal pregnancy and fetal growth restriction (FGR). Placental microvascular structure ultrasound imaging by MV-Flow was performed on 227 unaffected and 17 FGR fetuses between 11 and 41 weeks' gestation. A placental vascular index (VIMV ) was acquired by application of various MV-Flow regions of interest (ellipse, rectangle, and manual trace). Unaffected control and FGR groups were assessed for umbilical artery, middle cerebral artery, and uterine artery pulsatility indices and the cerebroplacental ratio calculated by ultrasound. No significant difference in the VIMV by varying regions of interest or placental regions was observed in the control group. The VIMV in the first trimester was lower than that in the second and third trimesters, with 5th through 95th percentile normal VIMV reference values of 18.39 to 63.79 for 13.6 weeks and earlier, 28.53 to 66.64 for 14 weeks to 27 weeks 6 days, and 21.95 to 67.45 for 28 weeks and later. The VIMV values in the FGR group were lower than those in the control group in the upper, middle, and lower parts of the placenta (mean ± SD, 24.9 ± 13.9 versus 45.0 ± 13.4; P < .01; 30.5 ± 16.1 versus 44.7 ± 14.3; P < .01; and 29.9 ± 17.4 versus 47.6 ± 12.2; P < .01, respectively). Higher umbilical artery and uterine artery pulsatility indices and a lower cerebroplacental ratio were found in the FGR group compared with the control group (P < .01). MV-Flow technology can display and quantify placental microvascular architecture at the level of the stem villi and villous leaves, and the VIMV provides for quantification of tissue vascularity. MV-Flow is a potentially powerful and promising tool to explore placental microvascular perfusion and provide new information on a host of pregnancy-related conditions.

MicroRNA-210 regulates placental adaptation to maternal hypoxic stress during pregnancy†.

MicroRNA (miR)-210 is a well-known hypoxia-inducible small RNA. Increasing in vitro evidence demonstrates its involvement in regulating multiple behaviors of placental trophoblasts. However, direct in vivo evidence remains lacking. In the present study, we generated a miR-210-deficient mouse strain using CRISPR/Cas9 technology, in which miR-210 expression was markedly deficient in various tissues. Little influence on fertility rate and litter size was observed after the deletion of miR-210 in mice. Continuous exposure of pregnant mice to hypoxia (10.5% O2) from E6.5 to E10.5 or to E18.5 led to reduction in fetal weight, and such fetal weight loss was markedly worsened in miR-210-knockout dams. Analysis of the placental structure demonstrated the reduced expansion of placental spongiotrophoblast layer and hampered development of labyrinth fetal blood vessels in knockout mice compared to the wild-type controls upon hypoxia stimulation. The findings indicate that miR-210 participates in regulating placental adaptation to hypoxic stress during pregnancy.

Development of the pig placenta*

Placental insufficiency results in fetal loss, low birth weight, stillbirth, preweaning mortality and poor growth. Placental development begins at conceptus elongation, which is a primary factor controlling the size of the placenta. After elongation, the allantois develops outward from the embryo to establish the allantochorion, which defines the size of the functional placenta. During implantation, chorionic trophoblasts adhere to endometrial epithelial cells. Placental structures known as areolae develop at the openings of the endometrial glands and take up endometrial gland secreted products (histotrophe). Between day 30 and 35 of gestation, the adhered trophoblast-endometrial epithelial bilayer undergoes microscopic folding. Fetal and maternal capillaries develop adjacent to the bilayer and blood flows are arranged in a cross-countercurrent manner. Except for nutrients secreted by the glands, nutrient exchange takes place between these capillaries within these folds. By day 85, the folds deepen and become more complex, increasing surface area. The epithelial bilayer thins and capillaries indent the plane of each layer (but do not penetrate), reducing distance between capillaries. The folded bilayer is surrounded by endometrial stroma on the maternal side and placental stroma on the fetal side. The fetal-placental stroma is partially composed of glycosaminoglycans, the most abundant being hyaluronan and heparan sulfate. Changes in both hyaluronoglucosaminidase and heparanase during placental development suggest that these enzymes play a role in placental development. In addition to structural modifications, various nutrient specific transport mechanisms exist. These mechanisms are likely to be as important to transport of specific nutrients as placental size or structure.

Histopathology of Third Trimester Placenta from SARS-CoV-2-Positive Women

Background: This study aims to investigate whether maternal SARS-CoV-2 status affects placental pathology. Methods: A retrospective case-control study was conducted by reviewing charts and slides of placentas delivered between April 1 to July 24, 2020. Clinical history of “COVID-19” was searched in Pathology Database (CoPath). Controls were matched with SARS-CoV-2-negative women with singleton deliveries in the 3rd-trimester. Pathological features were extracted from placental pathology reports. Results: Twenty-one 3rd trimester placentas from SARS-CoV-2-positive women were identified and compared to 20 placentas from SARS-CoV-2-negative women. There were no significant differences in individual or group gross or microscopic pathological features. Within the SARS-CoV-2+ group, there are no differences between symptomatic and asymptomatic women. Conclusion: Placentas from SARS-CoV-2-positive women do not demonstrate a specific pathological pattern. Pregnancy complicated with COVID-19 during the 3rd trimester does not have a demonstrable effect on placental structure and pathology.

Unique features and emerging in vitro models of human placental development.

BackgroundThe placenta is an essential organ for the normal development of mammalian fetuses. Most of our knowledge on the molecular mechanisms of placental development has come from the analyses of mice, especially histopathological examination of knockout mice. Choriocarcinoma and immortalized cell lines have also been used for basic research on the human placenta. However, these cells are quite different from normal trophoblast cells.MethodsIn this review, we first provide an overview of mouse and human placental development with particular focus on the differences in the anatomy, transcription factor networks, and epigenetic characteristics between these species. Next, we discuss pregnancy complications associated with abnormal placentation. Finally, we introduce emerging in vitro models to study the human placenta, including human trophoblast stem (TS) cells, trophoblast and endometrium organoids, and artificial embryos.Main findingsThe placental structure and development differ greatly between humans and mice. The recent establishment of human TS cells and trophoblast and endometrial organoids enhances our understanding of the mechanisms underlying human placental development.ConclusionThese in vitro models will greatly advance our understanding of human placental development and potentially contribute to the elucidation of the causes of infertility and other pregnancy complications.

Maternal oxycodone treatment causes pathophysiological changes in the mouse placenta

IntroductionPregnant women are increasingly being prescribed and abusing opioid drugs. As the primary communication organ between mother and conceptus, the placenta may be vulnerable to opioid effects but also holds the key to better understanding how these drugs affect long-term offspring health. We hypothesized that maternal treatment with oxycodone (OXY), the primary opioid at the center of the current crisis, deleteriously affects placental structure and gene expression patterns. MethodsFemale mice were treated daily with 5 mg OXY/kg or saline solution (Control, CTL) for two weeks prior to breeding and until placenta were collected at embryonic age 12.5. A portion of the placenta was fixed for histology, and the remainder was frozen for RNA isolation followed by RNAseq. ResultsMaternal OXY treatment reduced parietal trophoblast giant cell (pTGC) area and decreased the maternal blood vessel area within the labyrinth region. OXY exposure affected placental gene expression profiles in a sex dependent manner with female placenta showing up-regulation of many placental enriched genes, including Ceacam11, Ceacam14, Ceacam12, Ceacam13, Prl7b1, Prl2b1, Ctsq, and Tpbpa. In contrast, placenta of OXY exposed males had alteration of many ribosomal proteins. Weighted correlation network analysis revealed that in OXY female vs. CTL female comparison, select modules correlated with OXY-induced placental histological changes. Such associations were lacking in the male OXY vs. CTL male comparison. DiscussionResults suggest OXY exposure alters placental histology. In response to OXY exposure, female placenta responds by upregulating placental enriched transcripts that are either unchanged or downregulated in male placenta. Such changes may shield female offspring from developmental origins of health and disease-based diseases.

Placental 11β-HSD2 downregulated in HIV associated preeclampsia

Preeclampsia (PE) and human immunodeficiency virus (HIV) have been linked with marked increases in maternal stress, resulting in a significant change in placental function ranging from alterations in placental structure to the precise and delicate transformations in placental gene expression. Such changes may lead to altered transport of essential signals to the fetus, which can have long-term impacts on offspring health and consequently affect fetal neurodevelopment. Therefore, this work investigated the role of placental 11β-hydroxysteroid dehydrogenase types 2 (11β-HSD2) in HIV associated preeclampsia. The placenta were obtained from 76 pregnant women, which were stratified based on pregnancy type and HIV status into; Normotensive HIV negative, normotensive HIV positive, PE HIV negative and PE HIV positive. The placental tissue was processed for immunocytochemistry and stained with rabbit polyclonal to 11β-HSD2 Our results showed significant downregulation in the placental expression of 11β-HSD2 in both the conducting and exchange villi of PE and HIV-positive patients when compared with Normotensive and HIV-negative individuals, respectively. Our results provide inferential evidence for comorbidity of PE and HIV in the downregulation of placental 11β-HSD2 enzyme function, which mediates the programmed outcomes of an adverse maternal environment during pregnancy and long-term impacts on offspring health and consequently affects fetal neurodevelopment.