Transplacental transmission of HIV: a potential role for HIV binding lectins

Although the majority of vertical transmission of HIV occurs around the time of birth, 1.5-2% of pregnancies in HIV-positive women appear to result in the vertical transmission of HIV across the placenta. HIV infection of a number of placental cell types has been demonstrated, but the exact mechanisms of intrauterine vertical transmission remain obscure. The recent discovery of the HIV binding lectins dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN) and DC-SIGN-related molecule (DC-SIGNR) provides one possible explanation. Cells expressing these lectins are able to adsorb the virus and mediate high efficiency HIV infection of other cell types. Both lectins are expressed by the placenta, with DC-SIGN expression also being present on maternal cells intimately associated with the placenta. This review focuses on possible mechanisms by which these lectins may potentiate the intrauterine vertical transmission of HIV.     

The Effect of Antenatal Depression and Selective Serotonin Reuptake Inhibitor Treatment on Nerve Growth Factor Signaling in Human Placenta

Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT) exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF) is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12) and compared them with placenta from depressed (n = 12) and healthy mothers (n = 12). Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the clinical relevance of our findings still needs to be investigated.     

Histomorphometric changes in the placenta and umbilical cord during complications of pregnancy

Pregnancy complications may cause morphological changes and circulation defects in the placenta, which may lead to morbidity and mortality in fetuses and newborns. We investigated structural changes in the placenta and umbilical cord under various abnormal maternal conditions. Placenta and umbilical cord specimens were obtained from pregnant women during labor at 37 ? 42 weeks gestation. Volumetric measurements were made for each placenta and umbilical cord using the Cavalieri method. Significant differences were observed for volumetric densities of total villi, syncytial knots, intervillous vessels and perivillous fibrin deposition. We observed particular increases in the volumetric parameters of the pre-eclampsia group compared to the other groups. The tunica media of the umbilical arteries was increased significantly with intrahepatic cholestasis.     

Incidence and Risk Factors for Placenta Accreta/Increta/Percreta in the UK: A National Case-Control Study

Background

Placenta accreta/increta/percreta is associated with major pregnancy complications and is thought to be becoming more common. The aims of this study were to estimate the incidence of placenta accreta/increta/percreta in the UK and to investigate and quantify the associated risk factors.

Methods

A national case-control study using the UK Obstetric Surveillance System was undertaken, including 134 women diagnosed with placenta accreta/increta/percreta between May 2010 and April 2011 and 256 control women.

Results

The estimated incidence of placenta accreta/increta/percreta was 1.7 per 10,000 maternities overall; 577 per 10,000 in women with both a previous caesarean delivery and placenta praevia. Women who had a previous caesarean delivery (adjusted odds ratio (aOR) 14.41, 95%CI 5.63–36.85), other previous uterine surgery (aOR 3.40, 95%CI 1.30–8.91), an IVF pregnancy (aOR 32.13, 95%CI 2.03–509.23) and placenta praevia diagnosed antepartum (aOR 65.02, 95%CI 16.58–254.96) had raised odds of having placenta accreta/increta/percreta. There was also a raised odds of placenta accreta/increta/percreta associated with older maternal age in women without a previous caesarean delivery (aOR 1.30, 95%CI 1.13–1.50 for every one year increase in age).

Conclusions

Women with both a prior caesarean delivery and placenta praevia have a high incidence of placenta accreta/increta/percreta. There is a need to maintain a high index of suspicion of abnormal placental invasion in such women and preparations for delivery should be made accordingly.     

Development of the main and accessory placentae in the Japanese long-fingered bat, Miniopterus schreibersii fuliginosus

The placentae of the Japanese long-fingered bat were characterized by their morphological and functional transition from the main placenta to the accessory placentae. The main placenta transformed from an endotheliodichorial to a haemodichorial (one layer of syncytiotrophoblast and one layer of cytotrophoblast cells) condition. Degeneration of the main placenta was accompanied by development of two accessory placentae. These developed on both sides (fetal side) of the main placenta, and subsequently converted from a haemodichorial (two layers of cytotrophoblast cells) to a haemomonochorial condition.     

Increased levels of cell-free hemoglobin,oxidation markers,and the antioxidative heme scavenger α1-microglobulin in preeclampsia

Preeclampsia is a major cause of morbidity and mortality during pregnancy. To date, the pathogenesis of the disease is not fully understood. Recent studies show that preeclampsia is associated with overexpression of the hemoglobin genes α2 and γ and accumulation of the protein in the vascular lumen of the placenta. Hypothesizing that cell-free hemoglobin leaks from the placenta into the maternal circulation and contributes to the endothelial damage and symptoms by inducing oxidative stress, we analyzed fetal and adult hemoglobin (HbF, HbA), haptoglobin, oxidation markers, and the heme scavenger and antioxidant α₁-microglobulin in plasma, urine, and placenta in preeclamptic women (n = 28) and women with normal pregnancy (n = 27). The mean plasma concentrations of HbF, HbA, protein carbonyl groups, membrane peroxidation capacity, and α₁-microglobulin were significantly increased in preeclamptic women. The levels of total plasma Hb correlated strongly with the systolic blood pressure. The plasma haptoglobin concentrations of women with preeclampsia were significantly depressed. Increased amounts of α₁-microglobulin mRNA and protein were found in placenta from preeclamptic women, and the levels of plasma and placenta α₁-microglobulin correlated with the plasma Hb concentrations. The heme-degrading form t-α₁-microglobulin was significantly increased in urine in preeclampsia. These results support the idea that hemoglobin-induced oxidative stress is a pathogenic factor in preeclampsia.     

Comparative Proteomics Analysis of Placenta from Pregnant Women with Intrahepatic Cholestasis of Pregnancy

Introduction

Intrahepatic cholestasis of pregnancy (ICP) usually occurs in the third trimester and associated with increased risks in fetal complications. Currently, the exact cause of this disease is unknown. In this study we aim to investigate the potential proteins in placenta, which may participate in the molecular mechanisms of ICP-related fetal complications using iTRAQ-based proteomics approach.

Methods

The iTRAQ analysis combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to separate differentially expressed placental proteins from 4 pregnant women with ICP and 4 healthy pregnant women. Bioinformatics analysis was used to find the relative processes that these differentially expressed proteins were involved in. Three apoptosis related proteins ERp29, PRDX6 and MPO that resulted from iTRAQ-based proteomics were further verified in placenta by Western blotting and immunohistochemistry. Placental apoptosis was also detected by TUNEL assay.

Results

Proteomics results showed there were 38 differentially expressed proteins from pregnant women with ICP and healthy pregnant women, 29 were upregulated and 9 were downregulated in placenta from pregnant women with ICP. Bioinformatics analysis showed most of the identified proteins was functionally related to specific cell processes, including apoptosis, oxidative stress, lipid metabolism. The expression levels of ERp29, PRDX6 and MPO were consistent with the proteomics data. The apoptosis index in placenta from ICP patients was significantly increased.

Conclusion

This preliminary work provides a better understanding of the proteomic alterations of placenta from pregnant women with ICP and may provide us some new insights into the pathophysiology and potential novel treatment targets for ICP.     

妊娠期给予可卡因对母体和胎儿的影响: 小鼠动物模型

探讨妊娠期给予可卡因对母体和胎儿的影响。妊娠小鼠分为3组：可卡因注射组（每日两次注射盐酸可卡因10mg/kg,COC);盐水对照组（每日两次注射生理盐水10ml/kg,SAL);饮食对照组（每日两次注射生理盐水10ml/kg,饮食参考可卡因给药组,SPF）。用高压液相色谱分析法检测胎鼠血中可卡因浓度及纹状体中神经递质多巴胺和5－羟色胺的含量,并结合HE染色观察胎鼠肝脏和胎盘的形态学改变。尽管COC和SPF组母鼠摄食量和体重增长量均降低,但是仅仅COC组胎鼠的体重和脑重减少。高压液相色谱分析结果显示,在COC组胎鼠血浆中可检测出可卡因,并伴有纹状体神经递质含量的异常增高。同时,也观察到了COC组胎盘和肝脏的形态学变化。本研究表明,妊娠期给予可卡因能引起妊娠母体营养不良,子代脑、肝脏和胎盘发育异常;可卡因引起的胎儿发育异常是由可卡因的毒性作用而不是母体营养不良产生的。     

Immunoglobin-binding proteins in human placenta]

Phenomena of the binding of poor-soluble placenta proteins (PSPP) with pregnant women sera IgG as well as placenta blood IgG were studied. PSPP were extracted from the placenta tissue, washed out from soluble proteins, by the use of 3M KCl solution containing 0.005 M PMSF. PSPP were separated by the use of two-dimensional isoelectrofocusing and SDS-PAG electrophoresis and more than 30 different polypeptides were visualized. Having used various ELISA procedures with pregnant women sera IgG, placenta blood IgG as well as its Fab and Fc-fragments we have shown that both the receptor-type and the antigen-antibody-like interaction of PSPP took place. Both the polypeptide compositions and the isoelectrofocusing points ranges of the antigen-antibody-like interacting IgG-binding PSPP were determined by the use of the peroxidase conjugated Fab-fragments of the placenta blood IgG.     

Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta

Maternal hypercholesterolemia (HC) during pregnancy and gestational diabetes mellitus (GDM) are associated with disturbance of fetal development which may also modify key features of placental functions. In this study, we evaluated the impact of maternal hypercholesterolemia on placental cholesterol and lipid metabolism in 59 women classified in two groups according to the median concentration of plasma total cholesterol (6.42 mM). The impact of GDM was also evaluated on the metabolism of placentas obtained from 7 insulin-treated GDM and 7 non-GDM women. We showed that high maternal circulating cholesterol is associated with a significant increase in the LDL-cholesterol, ApoB-100 and triglyceride concentrations in the maternal blood. However the level of cholesterol in the venous cord blood and placenta remains unchanged in response to modification in maternal cholesterol profile. The levels of Fatty acid synthase (FAS) and SREBP-2 expressions in placenta are significantly increased in the HC group while expression of both sterol regulatory element-binding proteins-1 (SREBP-1) and HMG-CoA reductase (HMGR) are not modified. GDM is not associated with modification in the maternal lipid profile but it increases the concentration of inflammatory cytokines (IL-1beta and TNF-alpha) in placenta which correlates with a dramatic induction of FAS expression without affecting the expression of mature SREBPs proteins. In conclusion, our study suggests that in placenta, expressions of key proteins involved in de novo lipid synthesis are affected by changes in maternal metabolism (HC and GDM) that may subsequently affect fetal development.     

Placental triglyceride accumulation in maternal type 1 diabetes is associated with increased lipase gene expression

Maternal diabetes can cause fetal macrosomia and increased risk of obesity, diabetes, and cardiovascular disease in adulthood of the offspring. Although increased transplacental lipid transport could be involved, the impact of maternal type 1 diabetes on molecular mechanisms for lipid transport in placenta is largely unknown. To examine whether maternal type 1 diabetes affects placental lipid metabolism, we measured lipids and mRNA expression of lipase-encoding genes in placentas from women with type 1 diabetes (n = 27) and a control group (n = 21). The placental triglyceride (TG) concentration and mRNA expression of endothelial lipase (EL) and hormone-sensitive lipase (HSL) were increased in placentas from women with diabetes. The differences were more pronounced in women with diabetes and suboptimal metabolic control than in women with diabetes and good metabolic control. Placental mRNA expression of lipoprotein lipase and lysosomal lipase were similar in women with diabetes and the control group. Immunohistochemistry showed EL protein in syncytiotrophoblasts facing the maternal blood and endothelial cells facing the fetal blood in placentas from both normal women and women with diabetes. These results suggest that maternal type 1 diabetes is associated with TG accumulation and increased EL and HSL gene expression in placenta and that optimal metabolic control reduces these effects.     

Syncytiotrophoblast Extracellular Vesicles from Pre-Eclampsia Placentas Differentially Affect Platelet Function

Pre-eclampsia (PE) complicates around 3% of all pregnancies and is one of the most common causes of maternal mortality worldwide. The pathophysiology of PE remains unclear however its underlying cause originates from the placenta and manifests as raised blood pressure, proteinuria, vascular or systemic inflammation and hypercoagulation in the mother. Women who develop PE are also at significantly higher risk of subsequently developing cardiovascular (CV) disease. In PE, the failing endoplasmic reticulum, oxidative and inflammatory stressed syncytiotrophoblast layer of the placenta sheds increased numbers of syncytiotrophoblast extracellular vesicles (STBEV) into the maternal circulation. Platelet reactivity, size and concentration are also known to be altered in some women who develop PE, although the underlying reasons for this have not been determined. In this study we show that STBEV from disease free placenta isolated ex vivo by dual placental perfusion associate rapidly with platelets. We provide evidence that STBEV isolated from normal placentas cause platelet activation and that this is increased with STBEV from PE pregnancies. Furthermore, treatment of platelets with aspirin, currently prescribed for women at high risk of PE to reduce platelet aggregation, also inhibits STBEV-induced reversible aggregation of washed platelets. Increased platelet reactivity as a result of exposure to PE placenta derived STBEVs correlates with increased thrombotic risk associated with PE. These observations establish a possible direct link between the clotting disturbances of PE and dysfunction of the placenta, as well as the known increased risk of thromboembolism associated with this condition.     

Cytogenetic study of the chorion and placenta in prenatal diagnosis of fetal pathology]

The experience of investigation of 230 chorion and placental biopsy in 209 women of high risk pregnancy group is presented. Two methods of "direct" chromosomal analysis have been compared. Prospects and high economic efficiency of chorion and placenta studies as against other methods of prenatal diagnosis, great role in a decrease of prenatal disease and mortality are confirmed.     

Urocortin in human placenta and maternal plasma.

Plasma immunoreactive (IR-) urocortin (Ucn) and corticotropin-releasing factor (CRF) levels in pregnant women were measured by their specific radioimmunoassays after extraction. Although plasma IR-CRF levels were increased in pregnant women as compared to men and non-pregnant women, there was no difference of plasma IR-Ucn levels among groups. Ucn mRNA was detected in cytotrophoblasts and syncytiotrophoblasts by in situ hybridization. A reverse-phase high-performance liquid chromatography (HPLC) showed the major peak of IR-Ucn in placenta and plasma that had similar chromatographic mobility to synthetic Ucn1-40. These data suggest that Ucn is produced and processed into the same form of synthetic Ucn in placenta, but not secreted into maternal blood.     

Effects of Gestational Magnetic Resonance Imaging on Methylation Status of Leptin Promoter in the Placenta and Cord Blood

Over the past two decades, magnetic resonance imaging (MRI) has been widely used for diagnosis in gestational women. Though it has several advantages, animal and human studies on the safety of MRI for the fetus remain inconclusive. Epigenetic modifications, which are crucial for cellular functioning, are prone to being affected by environmental changes. Therefore, we hypothesized that MRI during gestation may cause epigenetic modification alterations. Here, we investigated DNA methylation patterns of leptin promoter in the placenta and cord blood of women exposed to MRI during gestation. Results showed that average methylation levels of leptin in the placenta and cord blood were not affected by MRI. We also found that the methylation levels in the placenta and cord blood were not affected by different magnetic fields (1.5T and 3.0T MRI). However, if pregnant women were exposed to MRI at 15 to 20 weeks of gestation, the methylation level of leptin in cord blood was visibly lower than that of pregnant women exposed to MRI after 20-weeks of gestation (P = 0.037). mRNA expression level of leptin in cord blood was also altered, though mRNA expression of leptin in the placenta was not significantly affected. Therefore, we concluded that gestational MRI may not have major effects on the methylation level of leptin in cord blood and the placenta except for MRI applied before 20 weeks of gestation.     

Heat Shock Protein 27 Is Spatially Distributed in the Human Placenta and Decreased during Labor

Placental oxidative stress is a feature of human labor. Heat shock proteins (HSPs) play a key role in cellular stress. We hypothesized that placental expression of the small HSP 27 would be altered during labor and expression would vary in different regions of the placenta. Six women in labor who delivered vaginally and 6 women not in labor, who were delivered by Cesarean section, were recruited. Four equally spaced pieces were sampled from the inner, middle and outer regions of each placenta (total 12 samples per placenta). HSP 27 expression was investigated by Western blot analysis and RT-PCR. For non-labor, there was less HSP 27 protein in the inner placenta region compared with both the middle region (p<0.05) and outer region (p<0.05). For labor, there was also less HSP 27 protein in the inner region compared with both the middle (p<0.02) and outer region (p<0.01). When the 3 regions of the placenta were compared for non-labor versus labor there was less HSP 27 in the labor group at both the inner (p<0.05) and middle regions (p<0.005) compared to non-labor. Similar to HSP 27 protein, there was less HSP 27 mRNA in the labor group in both the inner region (p<0.05) and middle region (p<0.02) compared to non-labor. This study suggests that placental HSP 27 may play a role in labor and is spatially controlled. The results have important implications for how data obtained from studies in the placenta can be influenced by sampling methods.     

Matrix metalloproteinase-1 and -9 in human placenta during spontaneous vaginal delivery and caesarean sectioning in preterm pregnancy

Preterm birth is a major public health problem in terms of loss of life, long-term and short term disabilities worldwide. The process of parturition (both term and preterm) involves intensive remodelling of the extracellular matrix (ECM) in the placenta and fetal membranes by matrix metalloproteinases (MMPs). Our previous studies show reduced docosahexaenoic acid (DHA) in women delivering preterm. Further omega 3 fatty acids are reported to regulate MMP levels. This study was undertaken to examine the placental levels of MMPs and their association with placental DHA levels in women delivering preterm. The levels of MMP-1 and MMP-9 in 74 women delivering preterm (52 by spontaneous vaginal delivery and 22 by caesarean sectioning) and 75 women delivering at term (59 by spontaneous vaginal delivery and 16 by caesarean sectioning) were determined by enzyme-linked immunosorbent assay (ELISA) and their association with placental DHA was studied. Placental MMP-1 levels were higher (p<0.05) in women delivering preterm (both by spontaneous vaginal delivery and caesarean sectioning) as compared to those delivering at term. In contrast, placental MMP-9 levels in preterm pregnancies was higher (p<0.05) in women with spontaneous vaginal delivery while lower (p<0.05) in women delivering by caesarean sectioning. Low placental DHA was associated with higher placental MMP-9 levels. Our study suggests a differential effect of mode of delivery on the levels of MMPs from placenta. Further this study suggests a negative association of DHA and the levels of MMP-9 in human placenta although the mechanisms need further study.     

Over-expression and secretion of angiogenin in intrauterine growth retardation placenta

Human angiogenin is a potent inducer of neovascularization. There is a strong evidence to suggest that it might be involved in morphological and angiogenic changes in the placenta, that are necessary for a successful fetal outcome during pregnancy. However, its precise role in the pathogenesis of abnormal pregnancies is yet unknown. Intrauterine growth retardation (IUGR), an abnormal pregnancy is not a specific disease entity per se, but rather a manifestation of many possible fetal and maternal disorders. In this study, we demonstrated, for the first time, that placental explants in vitro secrete significantly elevated levels of angiogenin in placental tissues from patients with IUGR. We also observed enhanced mRNA expression in placenta from these patients. In addition, using the immunohistochemical methods, we observed identical staining of angiogenin to villous syncytiotrophobalst and fetal endothelial cells in both IUGR and normal placenta. Functionally active placental explants were used to detect immunoreactive angiogenin in conditioned media of all the samples from IUGR placenta and normal term group. The mean levels of angiogenin secreted by IUGR placenta were 1.4-, 1.6-, and 1.3-fold higher (P < 0.01) than normal term samples at 24, 48, and 72 hr of culture, respectively. Expression profiles of angiogenin from term and IUGR cases are in agreement with its mRNA levels and immunoblot analysis. In conclusion, the significant elevated levels of angiogenin in IUGR placenta may provide a molecular mechanism for the abnormal placental development.     

产前经腹灰阶联合彩色血流超声多参数对胎盘植入性疾病的诊断效能研究

摘要 目的：探究产前经腹灰阶联合彩色血流超声多参数对胎盘植入性疾病的诊断效能。方法：2019年11月-2021年12月于我院收治的产前超声诊断为前置胎盘的孕妇共计62例,其中44例超声诊断合并了胎盘植入的孕妇。所有孕妇产前均进行经腹灰阶检查、经腹彩色超声检查和二者联合检查胎盘植入性疾病,通过分析胎盘植入性疾病筛查结果,评价产前超声经腹灰阶联合彩色血流超声多参数对胎盘植入性疾病的筛查效能。结果：（1）通过灰阶超声诊断检出胎盘植入的灵敏度为73.42 %,特异度为86.54 %;（2）通过彩色超声诊断检出胎盘植入的灵敏度为76.89%,特异度为89.07 %;（3）经腹灰阶联合彩色血流超声多参数诊断检出胎盘植入的灵敏度为87.79 %,特异度为90.36 %;（4）经腹灰阶检查、经腹彩色超声检查和二者联合检查对胎盘植入性疾病筛查阳性率分别为56.45 %、62.90 %和67.74 %,二者联合检查对产前胎盘植入性疾病筛查阳性率显著高于经腹灰阶检查和经腹彩色超声检查（P<0.05）。（5）二者联合检查的敏感度为72.26 %,特异度为90.54 %,阳性比为95.55 %,诊断比值比为78.89 %。结论：产前经腹灰阶联合彩色血流超声多参数对胎盘植入性疾病的诊断有较高的灵敏度和特异度,值得临床推广应用。