Pathogenesis Of Severe Preeclampsia Research Articles

Analysis of changes in high-mobility group box 1, receptor for advanced glycation endproducts, and T helper 17/regulatory T balance in severe preeclampsia with acute heart failure.

We measured the levels of High-Mobility Group Box 1 (HMGB1), Receptor for Advanced Glycation Endproducts (RAGE), T Helper 17 cells (Th17), Regulatory T cells (Treg), and related cytokines in the peripheral blood of patients with severe preeclampsia (SPE) complicated with acute heart failure (AHF) to explore the expression changes in these indicators. In total, 96 patients with SPE admitted to Gansu Provincial Maternity and Child-care Hospital between June 2020 and June 2022 were included in the study. The patients were divided into SPE+AHF (40 patients) and SPE (56 patients) groups based on whether they suffered from AHF. Additionally, 56 healthy pregnant women who either received prenatal examinations or were admitted to our hospital for delivery during the same period were selected as the healthy control group. An enzyme-linked immunosorbent assay was performed to detect the expression levels of HMGB1, RAGE, interleukin (IL)-17, IL-6, transforming growth factor β (TGF-β), IL-10, and NT-proBNP in plasma. Flow cytometry was employed to determine the percentages of Th17 and Treg cells. Compared to the healthy control group, the SPE+AHF and SPE groups had higher plasma levels of HMGB1 and RAGE expression, higher Th17 percentage and Th17/Treg ratio, and lower Treg percentage. Compared to the SPE group, the SPE+AHF group had higher plasma levels of HMGB1 and RAGE expression, higher Th17 percentage and Th17/Treg ratio, and lower Treg percentage (P<.05). In patients with SPE with AHF, plasma HMGB1 was positively correlated with RAGE, Th17, Th17/Treg, IL-17, and IL-6 and was negatively correlated with TGF-β and IL-10 (P<.05). Our findings revealed that patients with SPE with AHF had elevated levels of HMGB1 and RAGE while exhibiting Th17/Treg immune imbalance, suggesting that the abnormal expression of these indicators may be involved in the pathogenesis of SPE with AHF.

Cluster of differentiation 4/cluster of differentiation 8 ratio of T-lymphocyte subsets in Egyptian patients with severe pre-eclampsia

This study was designed to evaluate the immunological role of CD4+Tcells, CD8+ T cells in the pathogenesis of severe pre-eclampsia. Consequently, we estimated their blood levels and the CD4+/CD8+Tcells ratio among patients with pre-eclampsia. The study included 50 primigravid patients in third trimester, recruited from El-Shatby Maternity University Hospital. After obtaining informed written consents, they were divided into two groups: Group A included 25 patients with severe pre-eclampsia, and Group B included 25 normal pregnant women. All patients underwent thorough history taking, complete clinical examination and ultrasound evaluation for fetal condition. Then the percentages of blood CD4+ T cells and CD8+ T cells were estimated via flow cytometry and CD4+/CD8+ T cells ratio was calculated. Patients with severe pre-eclampsia in Group A revealed an increase in CD4+ T cells and a decrease of CD8+ T cells together with an increase in CD4+/CD8+ T cells ratio in comparison with the normal pregnancy (Group B). These differences were statistically significant (p=0.041, p=0.0001 and, p=0.0001, respectively). In addition, there was a positive correlation of blood CD4+ T cells, CD8+ T cells, CD4/CD8 T cells ratio and severe pre-eclampsia. In conclusion, estimation of the percentage of CD4+ T cells, CD8+ T cells and their ratio may be used as a marker to predict pre-eclampsia and confirm its severity.

Comparison Levels of Copper, Zinc, and Cu/Zn Ratio of in Pre-eclampsia and Normal Pregnancy

Introduction&#x0D; Preeclampsia is a syndrome that occurs in pregnancy, characterized by hypertension, proteinuria and edema. Zinc and copper are micronutrients that play a role in the performance of several important enzymes in the human body, such as CuZnSOD and ACE2 enzymes that play a role in the pathogenesis of severe preeclampsia. Zinc also plays a role in the kallikrein-kinin system in the formation of bradykinin which then acts as a vasodilator. This study plans to compare the level of copper (Cu), Zink (Zn), and Cu/Zn ratio in preeclamtic and normal pregnancy women.&#x0D; Method&#x0D; The study recruited 30 pregnant women with severe preeclampsia who were treated at Dr. Hasan Sadikin Bandung and 30 normal pregnant women at one of the Independent Practice Midwives in the Cibabat area, which was conducted in the period September 2021 - November 2021. This research was an analytical observational study with a cross sectional study design. Cu and Zn levels were examined using inductively coupleds plasma mass spectrometry (ICP-MS). Chi Square, student’s t test, Mann Whitney and multivariat analysis were used for statistical analysis.&#x0D; Results&#x0D; The results of this study showed that the average Cu levels were higher in severe preeclampsia (mean: 2.149 vs. 2.116 mol/L, p=0.728). The median Zn level in the subjects with severe preeclampsia was higher than in normal pregnancies (58 vs 49 g/dL, p&lt;0.001). The median Cu/Zn ratio in severe preeclampsia subjects was lower than in normal pregnancies (0.034 vs 0.063 g/dL, p=0.021).&#x0D; Conclusion&#x0D; Zn levels was significantly increased in the preeclampsia group, Cu levels was not significantly increased in the preeclampsia group and the ratio of Cu/Zn levels was significantly decreased in preeclampsia group compared to normal pregnancies.

Lysine (K)-specific demethylase 5C regulates the incidence of severe preeclampsia by adjusting the expression of bone morphogenetic protein-7

ABSTRACT This study aimed to investigate the roles of the lysine (K)-specific demethylase 5C (KDM5C)–bone morphogenetic protein-7 (BMP-7) signaling pathway in the pathogenesis of severe preeclampsia (sPE). A total of 180 pregnant patients were enrolled in the study and classified into three groups: an early-onset sPE group (EOsPE) (n = 60), a late-onset sPE group (LOsPE) (n = 60), and a control group (normal pregnancy; n = 60). The messenger RNA (mRNA) and protein expression levels of bone morphogenetic protein receptor II (BMPRII), BMP-7, and KDM5C were detected in placenta samples from the two sPE groups, and their sites were evaluated using immunohistochemistry (IHC). The sPE groups showed an increased KDM5C mRNA expression, and the EOsPE group showed a decreased BMP-7 and BMPRII mRNA expression compared with the LOsPE group. However, contradictory results were discovered in terms of protein expression. Immunostaining of KDM5C, BMP-7, and BMPRII was observed in villous trophoblast and extravillous trophoblast cells. Compared with the control group, the staining intensity of KDM5C in the placental tissue trophoblast cell nucleus and vascular endothelial cells of the sPE groups was weaker, while that of BMP-7 and BMPRII was stronger, and the staining intensity was more subjective in the LOsPE group. Consistent findings were obtained by IHC and Western blot analysis. KDM5C nuclear-cytoplasmic translocation may regulate sPE through BMP-7 and its receptors. The KDM5C–BMP-7 signaling pathway may also lead to less invasion and increased apoptosis of the trophoblast cells, which is involved in the pathogenesis of sPE.

Detection of mitochondrial coupling factor 6 in placental tissues from preeclamptic pregnancies and its influence on biological behavior of trophoblast cells

Increased levels of mitochondrial coupling factor 6 (CF6) are present in the peripheral blood of patients with preeclamptic pregnancies, and are particularly evident in cases of early-onset or severe preeclampsia. The present study examined the location and expression levels of CF6 in the placental tissue and its effect on the biological behavior of trophoblast cells. Placental tissue microarrays, including placental villous cytotrophoblast and extravillous cytotrophoblast microarrays, were used to detect the location and relative expression levels of CF6 in the placenta using immunohistochemistry. It was found that CF6 was expressed in both the normal and preeclamptic placenta, but its levels were higher in the preeclamptic tissues. In addition, the effects of the hypoxic environment on the biological behaviors of trophoblast cells were investigated in the JAR and JEG-3 cell lines. Following induction of hypoxia, the expression levels of CF6 were increased. Moreover, exogenous addition of human recombinant CF6 attenuated cell invasion, but exerted no effect on cell proliferation. At the molecular level, the expression levels of MMP-2 were decreased and were accompanied with a reduction in cell invasion following addition of exogenous CF6. In conclusion, the increased expression levels of CF6 and its effects in reducing the invasive abilities of trophoblast cells may be involved in the pathogenesis of severe preeclampsia.

Severe preeclampsia is associated with a higher relative abundance of Prevotella bivia in the vaginal microbiota

We sought to compare the vaginal microbiota profiles of Taiwanese women with severe preeclampsia (SPE) and normotensive control pregnancies. In a discovery cohort, vaginal swab samples and paired blood specimens were simultaneously obtained at the time of caesarean delivery from 30 women with SPE and 30 controls. The composition of vaginal microbiota was characterised by 16S ribosomal RNA gene sequencing of the V3–V4 region. Results were subsequently validated by real-time qPCR. We sought confirmation of our findings in an expanded cohort consisting of 58 women with SPE and 55 controls. In both the discovery and confirmation cohorts, women with SPE had higher relative abundance of Prevotella bivia in their vaginal microbial community (P = 0.006 and 0.011, respectively). Plasma levels of tumour necrosis factor alpha (TNF-α) were higher when compared with controls (P = 0.031) in the confirmation cohort. Three variables (vaginal Prevotella bivia, plasma TNF-α, and body mass index [BMI]) were included in a prediction panel for SPE. Of these, BMI was the most predictive variable. The area under the curve (AUC) of predicted probability values for the three-variable panel revealed that it can discriminate between SPE and normotensive pregnancies with good accuracy (AUC = 0.797, P < 0.001). We conclude that enrichment of Prevotella bivia in vaginal microbiota, which is tightly regulated by BMI, may be involved in the pathogenesis of SPE.

MiR-181a-5p suppresses invasion and migration of HTR-8/SVneo cells by directly targeting IGF2BP2

Pre-eclampsia is a pregnancy-related disease that may cause maternal, neonatal and fetal morbidity and mortality and exists in 3–5% of pregnancies worldwide. The discovery of dysregulated microRNAs and their roles in placental development has provided a new avenue for elucidating the mechanism involved in this pregnancy-specific disorder. Here, the roles of human miR-181a-5p, a microRNA that is increased in both the plasma and placenta of severe pre-eclamptic patients, in invasion and migration of trophoblasts were investigated. Ectopic-expression of miR-181a-5p impaired the invasion and migration of HTR-8/SVneo cells, whereas miR-181a-5p inhibition had the opposite effects. IGF2BP2, which harbors a highly conserved miR-181a-5p-binding site within its 3ʹ-UTR, was identified to be directly inhibited by miR-181a-5p. Moreover, siRNAs targeting IGF2BP2 imitated the effects of overexpressed miR-181a-5p on HTR-8/SVneo cell invasion and migration, whereas restoring IGF2BP2 expression by overexpressing a plasmid encoding IGF2BP2 partially reversed the studied inhibitory functions of miR-181a-5p. Thus, we demonstrated here that miR-181a-5p suppresses the invasion and migration of cytotrophoblasts, and its inhibitory effects were at least partially mediated by the suppression of IGF2BP2 expression, thus shedding new light on the roles of miR-181a-5p in the pathogenesis of severe pre-eclampsia.

Role of T helper 22 and 17 cells in pathogenesis of severe preeclampsia

Objective To investigate the role of T helper (Th) 22 and Th17 cells in the pathogenesis of severe preeclampsia. Methods Thirty women with severe preeclampsia who delivered in the Third Affiliated Hospital of Zhengzhou University from October 2014 to February 2016 were enrolled in the study. Thirty healthy pregnant women matched for age and gestational weeks were recruited as the control group. The frequencies of Th22 and Th17 cells in peripheral whole blood were determined by flow cytometry. The concentrations of interleukin (IL)-22 and IL-17A in plasma were detected by enzyme-linked immunosorbent assay. Independent two samples t-test, non-parametric test and Spearman correlation analysis were used for statistical analysis. Results The percentage of Th22 and Th17 cells in the severe preeclampsia group were significantly higher than those in the control group, respectively[Th22 cells: 0.59% (0.39%-1.13%) vs 0.40% (0.23%-0.57%), Z=2.530, P=0.010; Th17 cells: 3.24% (3.02%-3.97%) vs 1.87% (1.53%-2.64%), Z=5.046, P=0.000]. So were the plasma levels of IL-22 and IL-17A[IL-22: 285.72 (247.63-306.69) vs 233.85 (184.92-258.38) pg/ml, Z=4.341, P=0.001; IL-17A: 27.53 (23.84-32.78) vs 17.36 (15.58-19.13) pg/ml, Z=4.924, P=0.000]. There was a positive correlation between circulating Th22 and Th17 cells in the severe preeclampsia group (r=0.534, P=0.015), while no correlation was found in the control group (r=0.345, P=0.136). Positive correlation was found in plasma level of IL-22 with Th22 cells (r=0.600, P=0.005), but not with Th17 cells (r=0.398, P=0.082) in the severe preeclampsia group. Conclusions Increased Th22 cells and high IL-22 concentrations in the peripheral blood of severe preeclampsia patients may indicate a self-defense mechanism in the maternal body. Th22 cells and Th17 cells may interact with each other. Key words: Pre-eclampsia; T-lymphocytes, helper-inducer; Interleukins

Identification of a Novel Agonist-Like Autoantibody in Preeclamptic Patients.

Recent studies have shown that preeclampsia (PE) is associated with the presence of autoantibodies (AABs) that activate the angiotensin II AT1 receptor, which could contribute to many of the symptoms of PE. To investigate the frequency and the targets of AABs in preeclamptic women (31 cases) and healthy pregnant normotensive women (29 cases) in Brazil, antibodies from serum samples were detected by a bioassay using spontaneously beating neonatal rat cardiomyocytes in culture. In the cardiomyocytes, the agonistic AABs induce a positive or negative chronotropic response, mimicking the corresponding receptor agonists. The specificity of the AAB response was identified by specific receptor antagonists. Thirty preeclamptic patients (97%) presented AABs against the angiotensin II AT1 receptor. The agonistic effect of the AAB was blocked by irbesartan and neutralized by a peptide corresponding to the second extracellular loop of this receptor. Strikingly, we discovered that all sera from the severe preeclamptic patients (16 cases) contained a novel agonist-like AAB directed against the endothelin-1 ETA receptor in addition to the AABs against the angiotensin II AT1 receptor. This AAB was selectively blocked by the antagonist BQ-123, antagonized by the protein kinase C (PKC) inhibitor Calphostin C and neutralized by peptides corresponding to the second extracellular loop of the endothelin-1 ETA receptor subtype. We described, for the first time, the presence of endothelin-1 ETA receptor AABs in PE. Our results suggest that the presence of both agonistic AABs may be involved in the pathogenesis of severe PE.

Expression of interleukin-37 in placenta and its relationship with the pathogenesis of severe preeclampsia

To investigate the expression of interleukin-37 (IL-37) in placenta tissue and its relationship with the pathogenesis of severe preeclampsia. All the patients were recruited in Qilu Hospital of Shangdong University from November 2012 to November 2013. Among them, thirty patients with severe preeclampsia were assigned to the preeclampsia group, and thirty-one healthy pregnant women were assigned to the control group. Immunohistochemistry of SP was used to detect the IL-37 protein expression in placenta tissue of the two groups. The expression level of IL-37 in placenta tissue of the two groups was detected by western blot. Besides, reverse transcription (RT)-PCR was used to detect the expression of IL-37 mRNA. The correlation between the expression of IL-37 mRNA and the delivery gestational age, body mass index (BMI) was analyzed. (1) IL-37 were detected in the placenta of both the preeclampsia group and the control group, and the expression site mainly located in the syncytiotrophoblast, with a small amount in cytotrophoblast. (2) The expression levels of IL-37 protein in the preeclampsia group and the control group were 0.59 ± 0.39 and 0.88 ± 0.22, respectively. The IL-37 mRNA levels in the preeclampsia group and the control group were 0.55 ± 0.17 and 1.11 ± 0.21, respectively. Both decreased significantly when compared to the control group (P < 0.05). (3) Significant correlation between the expression of IL-37 mRNA and the delivery gestational weeks (r = 0.209, P > 0.05) was seen neither in the preeclampsia group nor in the control group (r = -0.053, P > 0.05). In the severe preeclampsia group, the pregnant women's BMI had no significant correlation with IL-37 mRNA expression of placenta tissue (r = 0.102, P > 0.05), neither did the control group(r = -0.115, P > 0.05). IL-37 expression is significantly lower in severe preeclampsia placenta tissue than that in the normal pregnant women, which may play a protective role in the course of severe preeclampsia.

Decreased expression and activation of Stat3 in severe preeclampsia

Severe preeclampsia (PE) is a major cause of maternal mortality and morbidity worldwide. Signal transducer and activator of transcription 3 (Stat3) signal pathway can modulate various fundamental cellular processes. However, whether Stat3 plays a role in the pathogenesis of severe PE is unknown. Therefore, in this study, the expression levels of Stat3 pathway-related genes and proteins, Stat3, pStat3, IL-6, Mcl-1L, Bcl-xL, survivin, MMP-2, and MMP-9, were evaluated by immunohistochemistry (IHC), Western blot analysis and real-time PCR in the severe preeclamptic placentas. Our results showed that Stat3 and pStat3 immunoreactivity were localized in both extravillous cytotrophoblast cells and villous trophoblast cells in the placentas. As compared with normotensive pregnancies, significantly decreased expressions of Stat3 and pStat3 proteins were observed in extravillous cytotrophoblast cells, villous trophoblast cells and entire placentas in patients with severe PE. The expression levels of Stat3, IL-6, survivin and MMP-2 mRNA were significantly decreased in severe preeclamptic placentas, while Mcl-1L, Bcl-xL and MMP-9 mRNA levels were unchanged. IHC results further confirmed that there was a significant decrease of IL-6, survivin and MMP-2 proteins expression in the severe preeclamptic placentas compared with the normal specimens. These findings suggested that decreased expression and activation of the Stat3 may be caused by decreased expression of a Stat3 upstream gene, such as IL-6. Decreased Stat3 expression and activation may play an important role in the pathogenesis of PE through regulation of the transcription of the Stat3 targeted genes survivin and MMP-2 to modulate apoptosis and invasion of placental trophoblastic cells.

Expression of markers of endoplasmic reticulum stress-induced apoptosis in the placenta of women with early and late onset severe pre-eclampsia

ObjectivesEndoplasmic reticulum (ER) stress-induced apoptosis has been implicated in severe pre-eclampsia (SPE) and is characterized by the activation of three signaling pathways: PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring 1 (Ire1). This study was designed to investigate the role of ER stress in the pathogenesis of SPE. Materials and methodsPlacental tissues were collected from 32 women with normal pregnancies and two cohorts of women with early (n = 32) or late onset (n = 32) SPE. The expression of glucose-regulated protein 78 (GRP78), PERK, eukaryotic initiation factor 2 subunit a (eIF2α), activating transcription factor 6 (ATF4), ATF6, Ire1, CHOP (ClEBP homologus protein), and caspase 12 mRNA and protein in the placentas was analyzed using real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. ResultsThe levels of GRP78, PERK, eIF2α, CHOP, ATF6, and caspase 12 mRNA and protein expression were significantly higher in the placentas of women with early and late SPE than in the control women, whereas there were no differences in ATF6 and Ire1 mRNA and protein. ConclusionER stress-induced apoptosis was important in the development of SPE, especially in early onset SPE and was probably due to the activation of the PERK signaling pathway.

Association of autoantibodies against the M2-muscarinic receptor with perinatal outcomes in women with severe preeclampsia.

BackgroundThe goal of this study was to test the hypothesis that autoantibodies against M2-muscarinic acetylcholine receptor (M2-AAB) are associated with severe preeclampsia and increased risk of adverse perinatal outcomes.MethodsWe conducted a case–control study comparing 60 women with severe preeclampsia to 60 women with normal pregnancy and 60 non-pregnant controls. A peptide, corresponding to amino acid sequences of the second extracellular loops of the M2 receptor, was synthesized as antigen to test for the presence of autoantibodies, using an enzyme-linked immunosorbent assay. The frequency and titer of M2-AAB were compared in the 3 groups. The risk of adverse perinatal outcomes among women with severe preeclampsia in the presence of M2-AAB was estimated.ResultsM2-AAB were positive in 31.7% (19/60) of patients with severe preeclampsia, in 10.0% (6/60) (p = 0.006) of normal pregnant women and in 8.3% (5/60) (p = 0.002) of non-pregnant controls. The presence of M2-AAB was associated with increased risk of adverse pregnancy complications (OR, 3.6; 95%CI, 1.0-12.6; p = 0.048), fetal growth restriction (OR, 6.8; 95% CI, 2.0-23.0; p = 0.002), fetal distress (OR, 6.7; 95% CI, 1.7-26.6; p = 0.007), low Apgar score (OR, 5.3; 95% CI, 1.4-20.7; p = 0.017), and perinatal death (OR, 4.3; 95% CI, 1.0-17.6; p = 0.044) among women with severe preeclampsia.ConclusionsThis study demonstrates, for the first time, an increase in M2-AAB in patients with severe preeclampsia. Women with severe preeclampsia who are M2-AAB positive are at increased risk for neonatal mortality and morbidity. We posit that M2-AAB may be involved in the pathogenesis of severe preeclampsia.

Maternal and Fetal Alternative Complement Pathway Activation in Early Severe Preeclampsia

We sought to determine whether alternative complement activation fragment Bb (Bb) levels are elevated in the maternal, fetal, and placental blood in cases of severe preeclampsia (PE) compared with normotensive controls. This was a cross-sectional study of women admitted at ≥24 weeks gestation with or without severe PE. Maternal plasma was collected at the time of enrollment. Umbilical venous cord and intervillous space blood were collected at delivery. Plasma Bb levels were assessed using ELISA. Bb levels were compared between cases and controls. Median Bb levels were higher in the maternal plasma of severe PE subjects (n = 24) than in controls (n = 20), 1.45 ± 1.03 versus 0.65 ± 0.23 μg/mL, P < 0.001. In umbilical venous plasma, Bb levels were higher in severe PE subjects (n = 15) compared with controls (n = 15), 2.48 ± 1.40 versus 1.01 ± 0.57 μg/mL, P = 0.01. Activation fragment Bb is increased in the maternal and umbilical venous blood of cases of severe PE when compared with normotensive controls. These data provide support for alternative complement pathway involvement in the pathogenesis of severe PE and demonstrate that alternative complement activation occurs not only in the maternal but also in the fetal compartment.

Placental expression of lipoprotein lipase and endothelial lipase in women with severe preeclampsia

Objective To investigate the effect of abnormal lipid metabolism in the pathogenesis of preeclampsia.Methods Thirty women with severe preeclampsia who delivered by cesarean section in the International Peace Maternity & Child Health Hospital from November 1,2011 to June 30,2012,were included as the study group.Thirty normal pregnant women delivered during the same period by cesarean section were included as the control group.The mRNA levels of lipoprotein lipase (LPL) and endothelial lipase (EL) in the placentas were quantified by real-time polymerase chain reaction.The expression of LPL/EL protein was detected by Western-blot assay and the distribution on the placenta was determined by immunohistochemical staining.The maternal serum level of lipid markers was detected by automatic biochemical analyzer.Difference between the two groups was compared with t-test or rank-sum test.Results (1) The triglyceride (TG) concentration [(3.35±0.80) mmol/L vs (2.75± 0.92) mmol/L,t =3.082,P=0.003] and atherosclerosis index (AI) (2.76±0.46 vs 2.47±0.34,t=3.066,P=0.003) increased in the study group compared with the control group,while the concentration of high-density lipoprotein-cholestrol (HDL-c) decreased[(1.64 ± 0.34) mmol/L vs (1.85 ± 0.22) mmol/L,t=-3.157,P =0.003].(2) The median level of LPL mRNA expression in placenta of the study group was higher than that of the control [1.26 (0.46-1.58) vs 0.52 (0.34-0.84),Z=-2.587,P=0.010],whereas the expression of EL mRNA was lower [0.65 (0.48-0.76) vs 1.32 (0.94-1.62),Z=-4.154,P=0.000].(3) Immunohistochemical analysis showed that the placenta EL and LPL located in cytoplasm of syncytiotrophoblast cells at the materno-placental interface and of endothelial cells at the feto-placental interface.(4) Compared with the control group,the median level of LPL protein expression in placenta inthe study group increased [0.68(0.46-0.83) vs 0.31(0.15-0.55),Z=3.335,P=0.001],and the expression of EL protein decreased [0.13 (0.11 0.16) vs 0.70(0.56 0.81),Z=-5.711,P=0.000].The expression of LPL protein was negatively correlated with that of EL protein (r=-0.501,P=0.000).Conclusions Abnormal lipid metabolism contributes to the pathogenesis of severe preeclampsia. Key words: Pre-eclampsia; Lipoprotein lipase; Endothelial lipase; Placenta

Association of Wnt2 and sFRP4 Expression in the Third Trimester Placenta in Women With Severe Preeclampsia

The Wnt signaling pathway is a conserved pathway and plays a crucial role in regulating trophoblast functions. Abnormal expression of the Wnt pathway may result in the dysfunction of the trophoblast that can contribute to the pathogenesis of preeclampsia (PE). However, published data regarding the association between Wnt pathway and PE in human pregnancy is rare. The aims of this study were to investigate the expression pattern of Wnt2 and secreted frizzled-related protein 4 (sFRP4) in the third trimester human placenta and to evaluate the relationship between changes in placental Wnt2 and sFRP4 expression and severe PE. The expression of Wnt2 and sFRP4 in normal and severe PE placentas was examined using immunohistochemistry (IHC), real-time polymerase chain reaction, and Western blot. Compared to the controls, the relative expression of Wnt2 messenger RNA was remarkably downregulated in the PE placentas, while there was no significant difference in sFRP4 between the 2 groups. The IHC indicated that Wnt2 and sFRP4 were expressed predominantly in the villous syncytiotrophoblast and the extravillous trophoblast, whereas Wnt2 in the control group showed higher staining intensity than in the PE group, and sFRP4 in the PE group had a higher staining intensity than in the control group. Furthermore, the results of the Western blots were consistent with the IHC. The Wnt signaling pathway was detected in human third trimester placentas, and the decreased placental expression of Wnt2 and increased placental expression of sFRP4 may be associated with the pathogenesis of severe PE.

GW24-e0800 Autoantibody against the M2-muscarinic receptors in patients with severe preeclampsia: a pilot study

ObjectivesPreeclampsia is the leading cause of maternal and neonatal morbidity and mortality with incompletely understood pathogenesis. The purpose of the current study is to determine whether there is a relationship...

Association between the Presence of Autoantibodies against Adrenoreceptors and Severe Pre-Eclampsia: A Pilot Study

BackgroundPre-eclampsia is the leading cause of maternal and neonatal morbidity and mortality with incompletely understood etiopathogenesis. The purpose of the current study is to determine whether there is a relationship between the presence of autoantibodies against β1, β2 and α1 adrenoreceptors and severe pre-eclampsia.Methodology/Principal FindingsSynthetic peptides corresponding to amino acid sequences of the second extracellular loops of β1, β2 and α1 adrenoreceptors were synthesized as antigens to test 34 patients with severe pre-eclampsia, 36 normal pregnancy women and 40 non-pregnant controls for the presence of autoantibodies using enzyme-linked immunosorbent assay. The respective frequencies of autoantibodies against β1, β2 and α1 adrenoreceptors were 50.0% (17/34), 52.9% (18/34) and 55.9% (19/34) in patients with severe pre-eclampsia, 19.4% (7/36) (p = 0.011), 19.4% (7/36) (p = 0.006) and 17.6% (6/36) (p = 0.001) in normal pregnancy women and 10% (4/40), 7.5% (3/40) and 10% (4/40) (p<0.001) in non-pregnant controls. Titers of these autoantibodies were also significantly increased in patients with severe pre-eclampsia. By logistic regression analysis, the presence of these three autoantibodies significantly increased the risk of neonatal death (odds ratio, 13.5; 95% confidence interval, 1.3–141.3; p = 0.030) and long-term neonatal hospitalization (odds ratio, 5.0; 95% confidence interval, 1.3–19.1; p = 0.018). The risk of hypertension and fetal distress were also associated with the presence of these three autoantibodies.Conclusions/SignificanceThis novel pilot study demonstrated for the first time that the presence of autoantibodies against β1, β2 and α1 adrenoreceptors are increased in patients with severe pre-eclampsia. Pregnant women who are positive for the three autoantibodies are at increased risks of neonatal mortality and morbidity. We posit that these autoantibodies may be involved in the pathogenesis of severe pre-eclampsia.

Expression of vitronectin in placental basal plate and its relationship with the pathogenesis of severe preeclampsia

To investigate the expression of vitronectin (VN) in placental basal plate and its relationship with the pathogenesis of severe preeclampsia. From March 2010 to December 2011, 17 patients with early-onset severe preeclampsia who delivered in the Second Hospital of Jilin University were recruited as the early-onset severe preeclampsia group; and 16 women were recruited as the late-onset severe preeclampsia group. Meanwhile, 15 healthy pregnant women who delivered before 34 weeks were defined as the early control group (termination of pregnancy was carried out because of fetal heart malformations), and 15 healthy pregnant women delivered after 34 weeks were defined as the late control group. Immunohistochemistry and semi-quantitative reverse transcription (RT)-PCR were used to investigate the expression of VN protein and mRNA in the placental infarct center and its surrounding tissue of placental basal plate. The levels of serum prothrombin time (PT), part thromboplastin time (APTT) and fibrinogen (FIb) were detected and the international normalized ratio (INR) was calculated. The correlation of abnormal coagulation markers and VN expression levels in the early-onset severe preeclampsia group and the early control group was studied. (1) VN protein was detected in all placental basal plate of the four groups. It was highly expressed in the necrotic tissue of placental infarct center and weakly expressed in the tissue far from the infarcted area. (2) The mean levels of VN protein expression in placental basal plate of the early-onset severe preeclampsia group, the late-onset severe preeclampsia group, the late control group and the early control group were 0.152 ± 0.019, 0.113 ± 0.023, 0.095 ± 0.014 and 0.055 ± 0.010, respectively. And the differences between the groups were statistically significant (P < 0.01). The VN protein expression in placental infarct center, infarct edge, peri-infarct tissue and tissue far from the infarcted area gradually reduced, and the differences were statistically significant (P < 0.01). Compared with the same areas of each group, the differences were not statistically significant (P > 0.05). (3) VN mRNA were detectable in infarct center, infarct edge, per-infarct tissue and tissue far from the infarcted area of placental basal plate. In the early-onset severe preeclampsia group and the early control group, it was statistically higher in infarct center than in tissue far from the infarcted area (P < 0.05). (4) PT of the early-onset severe preeclampsia group was (9.45 ± 0.63) s, significantly shorter than that of the early control group [(9.88 ± 0.17) s, P < 0.05]. While there was no statistically significant difference in APTT, FIB and INR among the four groups (P > 0.05). (5) In the early-onset severe preeclampsia group, VN expression level and PT were significantly negative correlated (r = -0.612, P < 0.05); while in the early control group there was no correlation (r = 0.489, P > 0.05). VN was highly expressed in placental basal plate of the early-onset severe preeclampsia group, which caused the imbalance of coagulation and fibrinolysis system and the pathogenesis of severe preeclampsia.

MTHFR C677T and eNOS G894T variants in preeclamptic women: Contribution to lipid peroxidation and oxidative stress

ObjectivesWe aimed to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T and endothelial nitric oxide synthase (eNOS) G894T polymorphisms with lipid peroxidation, total antioxidant capacity (TAC) and the risk of preeclampsia in preeclamptic women. Design and MethodsWe screened a sample of 198 unrelated women with mild and severe forms of preeclampsia and 101 unrelated women with normal pregnancy with the eNOS and MTHFR variants using PCR-RFLP method. Also, the serum malondialdehyde (MDA) and TAC levels were determined using HPLC and commercial kits, respectively. ResultsThe frequency of combined genotypes of MTHFR CT and TT (CT+TT) and T allele tended to be higher in severe preeclamptic women compared to controls. There was no significant difference for eNOS G894T genotype and allele frequencies between patients and controls. A significantly higher level of triglycerides was observed in the presence of combined genotypes of MTHFR CT and TT and also eNOS GT and TT (GT+TT) in preeclamptic women compared to controls with the same genotype. Also, the presence of MTHFR TT genotype in severe preeclamptic women was significantly associated with the increased serum MDA level compared to CC genotype. In severe preeclamptic women the presence of CT and combined genotypes of CT and TT was significantly associated with the decreased TAC level compared to CC genotype. Also, a higher MDA level was observed in mild preeclamptic women with eNOS TT genotype compared to those with GG genotype but the difference was not significant. ConclusionThe present study indicates that MTHFR C677T polymorphism through affecting on TG level, lipid peroxidation and oxidative stress might be involved in the pathogenesis of severe preeclampsia.