Circulating endothelial progenitor cells and placental abruption in women with preeclampsia

ObjectiveAbnormalities in circulating angiogenic factors and endothelial progenitor cells (EPCs) have been reported in patients with preeclampsia and placental abruption. The objective of this study was to determine whether the number of EPCs is altered in patients with placental abruption.DesignA case control study.SettingHiroshima University Hospital in Japan.SamplePregnant Japanese women with preeclampsia (n = 27) and those without any complications (n = 15).MethodThe EPC (CD45^lowCD34⁺CD133⁺ cells) counts were examined using flow cytometry in peripheral blood collected from 27 women with preeclampsia and 15 normal pregnant women. Among the 27 women with preeclampsia, five subsequently developed placental abruption. All subjects were divided into three groups: normal pregnancy (NP, n = 15), preeclampsia without placenta abruption (PE, n = 22) and preeclampsia with placental abruption (PA, n = 5).Main outcome measuresThe EPC counts were measured in pregnant women with preeclampsia who subsequently developed placental abruption.ResultsThe EPC count in the PE group significantly decreased in comparison to that observed in the NP group (620 cells/ml versus 1918 cells/ml, P < 0.01). In the PA group, the EPC count was found to markedly decrease in comparison to that observed in the PE group (221 cells/ml, P < 0.05).ConclusionsThe number of EPCs was found to significantly decrease in preeclamptic women who subsequently developed placental abruption.     

Alteration in IFN-γ and CCL2 serum levels at first trimester of pregnancy contribute to development of preeclampsia and fetal growth restriction

ObjectivePregnancy is a unique challenge for the immune system. Any disturbance in the immune system in the first trimester could result in further pregnancy complications. In this regard, the current study aimed to investigate the association between serum levels of a group of cytokines in the first trimester of pregnancy with the onset of preeclampsia (PE) and fetal growth restriction (FGR).Materials and methodsSerum samples were collected from 550 pregnant women at their 11th - 13th weeks of pregnancy and followed up to delivery. Out of all cases, 15 women complicated with preeclampsia and 15 ones diagnosed with FGR were included in the study. The serum levels of IFN-γ, CCL2, IL-10, IL-35 and IL-27 were checked in the collected sera of mentioned patients and compared to 60 women with normal pregnancy outcomes.ResultsIn the preeclampsia group, the mean level of IFN-γ was significantly higher (p < 0.001) while the CCL2 serum level was significantly lower (p < 0.003) as compared to control group. There was no significant difference between the preeclampsia group and controls regarding other cytokines. In the FGR group, the mean serum level of IFN-γ was significantly higher compared to the healthy pregnancy group (p < 0.001) but other cytokines showed no significant differences. In the FGR group, a significant positive correlation was found between IL-10 level and neonates' weight (p < 0.05).ConclusionBased on the results of the present study, an elevated level of IFN-γ and a reduced level of CCL2 at the first trimester of pregnancy could lead to complications such as PE and/or FGR.     

Plasma IL-17, IL-35, interferon-γ, SOCS3 and TGF-β levels in pregnant women with preeclampsia,and their relation with severity of disease

Abstract

Objective: To research the hypothesis of preeclampsia (PE) is associated with increased systemic inflammatory responses of Th1-type as well as decreased Th2-type responses; we evaluated the maternal plasma levels of IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, IL-10, IL-17, IL-35 and SOCS3 in preeclamptic and healthy pregnants.

Methods: This study was conducted with 40 preeclamptic (study group) and 40 normotensive pregnant (control) women in third trimester when they were admitted to the labor and delivery unit. The extracted maternal plasma samples were assayed by an enzyme-linked immunosorbent assay. Statistical analysis was performed by SPSS 16.0 version.

Results: While IFN-gamma and TGF-beta levels of preeclamptic women were significantly higher (p?<?0.01), IL-35 and IL-17 levels of preeclamptic women were significantly lower (p?<?0.01) than those of controls. The ratios of IFN-gamma/IL-10, IFN-gamma/IL-6, IFN-gamma/IL-4 were significantly high and ratio of IL-35/IL-17 was significantly low in the PE group compared to those in the control group. Maternal plasma SOCS3 levels showed negative correlation with blood pressure and proteinuria severity, but none of the cytokines showed influence on blood pressure and proteinuria after adjusting for maternal and gestational age.

Conclusions: Increased IFN-gamma/TGF-beta production and reduced IL-35/IL-17/SOCS3 production in preeclamptic women may lead to less cytokine inhibitory activity in PE, which may account for the increased proteinuria and blood pressure in PE.     

Expression and significance of dendritic cells and Th17/Treg in serum and placental tissues of patients with intrahepatic cholestasis of pregnancy

Purpose: Dendritic cells (DCs) are involved in immune system, which can also regulate the differentiation of T helper 17 (Th17) and regulatory T cells (Treg). DCs and Th17/Treg participate in preeclampsia and recurrent spontaneous abortion (RSA), but there is still lack of research in intrahepatic cholestasis of pregnancy (ICP). The aim was to evaluate the expression and significance of CD83⁺DCs, CD1a⁺DCs, interleukin-17 (IL-17) and IL-35 in serum and placental tissues of patients with ICP.

Methods: Thirty cases of mild ICP, 25 cases of severe ICP were selected, and 30 cases of normal pregnant women were selected as control group. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were used to detect the expression of CD83⁺DCs, CD1a⁺DCs, IL-17 and IL-35 in serum and placenta tissues, respectively.

Results: There were more CD83⁺DCs, IL-17 expressed in placenta from women with ICP than in normal pregnancies, while the number of decidual CD1a⁺DCs, IL-35 was significantly lower in ICP than in normal pregnant women. The comparison within three groups had statistical difference (p?+DCs and CD1a⁺DCs levels had no significance. IL-17 was higher in ICP, while IL-35 was lower.

Conclusions: DCs are involved in damaging the maternal–fetal immune tolerance by changing the phenotype and mature state, which may affect the differentiation of Th17/Treg to cause ICP.     

Elevated Serum Levels of Interleukin-15, Interleukin-16, and Human Chorionic Gonadotropin in Women With Preeclampsia

ObjectivesWe sought to investigate the relationship between serum levels of interleukin 15 (IL-15), interleukin 16 (IL-16), and human chorionic gonadotropin (β-hCG) in women with a normal pregnancy and with preeclampsia, and their association with disease severity. We also wished to calculate the accuracy of these markers in diagnosing the disease and predicting its severity.Materials and MethodsThe study was conducted at Al Fayoum University in Cairo between December 2006 and September 2007. Thirty-two primigravid women with preeclampsia (preeclamptic group) scheduled for Caesarean Section were recruited and matched for age and duration of pregnancy with 35 normotensive primigravid women (control group). Of the preeclamptic women, 18 had severe preeclampsia, and 14 had mild preeclampsia. Blood sampling was performed for assays of serum IL-15, IL-16, and β-hCG.ResultsSerum concentrations of IL-15, IL-16, and β-hCG were significantly greater in preeclamptic women than in normotensive pregnant women (P < 0.001). Moreover, they were significantly higher in women with severe preeclampsia than in mild cases (P < 0.001). There was a positive correlation between serum IL-15, IL-16, and β-hCG among all groups. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of serum β-hCG in predicting preeclampsia were 56.25%, 91.43%, 85.71%, 69.57%, and 74.63%, respectively. These values for IL-15 were 94.44%, 89.8%, 77.27%, 97.78%, and 91.04%, respectively, and for IL-16, the values were 88.89%, 95.92%, 88.89%, 95.92%, and 94.03%, respectively.ConclusionSerum levels of IL-15, IL-16, and β-hCG were significantly increased in preeclamptic women compared with normotensive women, and these levels correlated with disease severity. However, serum IL-15 and 16 had a greater overall accuracy than β-hCG in diagnosing severe preeclampsia.     

How accurate are placental growth factor,urate, lactate dehydrogenase and proteinuria in diagnosing preeclampsia and its severity?

ObjectiveThe objective was to assess the diagnostic accuracy of serum and urinary placental growth factor (sPlGF and uPlGF, respectively), urate, lactate dehydrogenase (LDH), and proteinuria for diagnosing and differentiating between women with preeclampsia and women with a normal healthy pregnancy, gestational hypertension, and gestational proteinuria.Study designUrine and blood samples were taken from pregnant women diagnosed with late-onset severe preeclampsia (30 patients), mild preeclampsia (30 patients), gestational hypertension without meeting the criteria for preeclampsia (30 patients), gestational proteinuria without meeting the criteria for preeclampsia (30 patients), and healthy pregnant control women (30 patients). A receiver operating characteristic (ROC) curves analysis was performed to evaluate the diagnostic accuracy and to select the optimal cutoff points for different markers.ResultssPlGF is the best test for differentiating women with severe preeclampsia from women in all of the other groups (p = 0.001). However, there was no significant difference between sPlGF and proteinuria in the 24-h urine collection (p = 0.329) in this differentiation. uPlGF can be used to differentiate women with severe preeclampsia from women in all of the other groups. However, proteinuria in the 24-h urine collection is better than uPlGF for this differentiation (p = 0.013).ConclusionsPlGF and uPlGF can be used to diagnose women with severe preeclampsia and should be considered at least as important as proteinuria in the diagnosis of preeclampsia. A large study that considers the cost-effectiveness of adding these markers to the diagnosis of preeclampsia should be conducted before our recommendation is applied.     

Serum S100B in pregnancy complicated by preeclampsia: A case-control study

BackgroundSerum S100B is a protein produced and released primarily by astrocytes of the Central Nervous System (CNS). Elevated levels of serum S100B are associated with several types of pathological conditions of the brain, including the eclampsia in pregnant women. The aim of this study was to compare serum S100B concentrations in pregnant women with severe and mild preeclampsia (PE) with S100B serum levels in normotensive pregnant women.Material and methodsSerum S100B protein was measured in normotensive pregnant women (n = 15) and in women with mild PE (n = 12) or severe PE (n = 34). The serum S100B level (μg/L) was determined by an luminometric assay.ResultsSixty-one expectant mothers were studied, aged 26.6 ± 8.7 (mean ± SD) years and with a gestational age of 33.3 ± 4.2 weeks. The severe PE group demonstrated higher S100B levels (0.20 ± 0.19), as compared with mild PE (0.07 ± 0.05) or normotensive groups (0.04 ± 0.05).ConclusionElevated serum S100B levels in pregnant women with severe PE suggest that some kind of neural damage and subsequent astrocytic release of S100B is not dependent on the progression from severe preeclampsia to eclampsia.     

Plasma IL-4, IL-8, IL-12, interferon-γ and CRP levels in pregnant women with preeclampsia,and their relation with severity of disease and fetal birth weight

Objective: The aim of the present study was to evaluate the hypothesis that preeclampsia is associated with increased systemic inflammatory responses of Th1-type as well as decreased Th2-type responses compared with normal pregnancy. We also sought to determine whether there was a correlation between these markers with severity of preeclampsia and fetal birth weight. Methods: The study population consisted of maternal age, gestational age, and body mass index matched 138 pregnant women; 56 normotensive healthy pregnant women (group 1), 42 women with mild preeclampsia (group 2), 40 women with severe preeclampsia (group 3). Results: Plasma interleukin (IL)-8 and C-reactive protein (CRP) levels were significantly higher in group 3 than group 1 (p?<?0.05). Plasma IL-4, IL-12, and interferon (IFN)-γ levels were similar in all groups. Although plasma IL-8 and CRP levels of mild preeclamptic group were higher than control group and lower than severe preeclamptic group, the differences were not statistically significant. There was a positive correlation between IL-12 and fetal birth weight in severe preeclamptic group (p?<?0.05). Conclusions: Elevated maternal serum pro-inflammatory cytokine IL-8 and CRP in severe preeclamptic women compared with normal pregnant women supports the hypothesis that preeclampsia is associated with increased inflammatory responses.     

Comparison of maternal serum levels of interleukin-10, interleukin-12, and interleukin-2 in normal and preeclamptic pregnancies

ObjectiveThe aim of this study was 2 fold: (1) to compare the maternal serum levels of IL-10, IL-12, and IL-2 in preeclamptic and normal pregnant women, and (2) to study the serum levels of these cytokines in preeclamptic pregnancies with and without intrauterine growth retardation.Study designForty women with singleton pregnancies complicated by preeclampsia (32 severe and 8 mild) and 29 normotensive healthy pregnant women were included in the study. Preeclamptic patients were further divided into 2 groups according to the presence or absence of intrauterine growth retardation. Maternal serum levels of IL-10, IL 12, and IL-2 were compared between these groups using enzyme-linked immunosorbent assays.ResultsMaternal serum levels of IL-10 were significantly higher in the preeclampsia group than in controls (p < 0.001). There were no statistically significant differences in maternal serum concentrations of IL-2 and IL-10 between the study and control groups (p > 0.05). Serum levels of IL-2 and IL-10 in the patients with preeclampsia complicated by IUGR were elevated in comparison with the uncomplicated preeclampsia group. These differences were statistically significant (p < 0.05 for both).ConclusionsIL-10 may be involved in the pathologic process of preeclampsia. Increased serum levels of IL-10 and IL-2 in preeclampsia complicated with IUGR suggests a possible role of these cytokines in IUGR.     

Association of first-trimester angiogenic factors with placental histological findings in late-onset preeclampsia

ObjectiveTo explore in women with late-onset preeclampsia (PE) the association between maternal levels of angiogenic/antiangiogenic factors in the first trimester of pregnancy and histological findings attributable to placental underperfusion (PUP).MethodsA nested case-control cohort study was conducted in 73 women with pregnancies complicated by late-onset PE (>34 weeks at delivery) matched with controls. First trimester uterine artery Doppler (UtA); maternal levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were retrieved. Placentas were histologically evaluated using a hierarchical and standardized classification system. One-way ANOVA with linear polynomial contrast or linear-by-linear association test was performed to test the hypothesis of a linear association across study groups (controls, PE without PUP and PE with PUP).ResultsIn 54 (74%) placentas, 89 placental histological findings qualifying for PUP were found. Across study groups, significant values were observed in maternal levels of decreased PlGF (MoM values: 1.53, 1.41 and 1.37; p < 0.001), increased sFlt-1 (MoM values: 3.11, 3.11 and 3.22; p = 0.002), increased sFlt-1/PlGF ratio (MoM values: 2.3, 2.3 and 2.44; p < 0.001), abnormal UtA Doppler (MoM values: 1, 1.26 and 1.32; p < 0.001), and worse perinatal outcomes in terms of gestational age at delivery, cesarean section for not reassuring fetal status, birth weight and neonatal acidosis.DiscussionIn late-onset PE an imbalance of circulating angiogenic and anti-angiogenic factors already present at 8–10 weeks of pregnancy was associated with histological findings reflecting placental insufficiency. An early first trimester screening by angiogenic factors might help to identify patients with placental involvement among late-onset PE cases.ConclusionIn late-onset preeclampsia, first-trimester uterine Doppler and circulating levels of angiogenic/antiangiogenic factors are associated with placental underperfusion.     

Alterations of IL-6, IL-6R and gp130 in early and late onset severe preeclampsia

Objective: Interleukin-6 (IL-6) and its receptor complex participate in a number of critical biological activities through several signaling pathways. Placental dysfunction and increased inflammation are believed to underlie the pathogenesis of severe preeclampsia (PE), which may involve IL-6-induced signaling. We investigate whether the changes in the expression of IL-6 and its cognate receptors, IL-6 receptor (IL-6R) and glycoprotein (gp)130, occur between early and late onset severe PE. Methods: A total of 18 healthy gravidas and 41 severe preeclamptic women were recruited, including 20 pregnancies with early onset and 21 pregnancies with late onset. The IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) levels in maternal and umbilical cord sera were tested by enzyme-linked immunosorbent assay; the immunoactivities of IL-6, IL-6R and gp130 in the placentas were determined by immunohistochemistry and immunoblotting. Results: We found that (1) maternal serum IL-6 and sIL-6R levels were increased, whereas sgp130 was decreased in women with early onset severe PE compared with those with late onset severe PE and normal controls. In contrast to normal controls, IL-6 and sIL-6R expression was up-regulated in late onset severe PE, and similar alterations of IL-6 and its soluble receptors were detected in early and late onset severe PE umbilical sera and (2) compared with late onset severe PE, reduced IL-6 and IL-6R but not gp130 expression was observed in early onset severe PE placentas. Conclusion: These results suggest a probable contributing role of alterations in IL-6 and its corresponding receptors to the pathophysiology of early and late onset severe PE.     

Placental expression and serum levels of cytokeratin-18 are increased in women with preeclampsia

OBJECTIVE: To evaluate placental expression and serum cytokeratin-18 in women with preeclampsia. METHODS: Serum cytokeratin-18 was evaluated in 44 women with preeclampsia and 44 healthy pregnant women using an immunoradiometric assay. Placental expression of cytokeratin-18 was investigated in specimens from 23 women with preeclampsia and 20 healthy pregnant women by immunohistochemistry. RESULTS: Median serum cytokeratin-18 in women with preeclampsia and healthy pregnant women was 106.7 and 76.0 U/L, respectively (P =.02). Among women with preeclampsia, serum cytokeratin-18 was significantly associated with severity of disease (P =.001) and showed a sensitivity (standard error) and specificity (standard error) of 85% (7%) and 65% (12%), respectively. In placental specimens, the cytoplasm of the syncytiotrophoblast stained positive for cytokeratin-18 with strong and widespread staining in 83% and 45% of placental specimens of women with preeclampsia and healthy pregnant women, respectively (P =.01). CONCLUSION: Elevated serum cytokeratin-18 values are associated with disease severity in women with preeclampsia. Our data provide additional evidence that the placenta might be the source of the elevated serum cytokeratin-18 values in women with preeclampsia.     

Expectant management of severe preeclampsia with severe fetal growth restriction in the second trimester

ObjectiveWe investigated whether women with severe fetal growth restriction (FGR <5th percentile) associated with severe preeclampsia (PE) occurring in the second trimester are candidates for expectant management.Study designThis is a retrospective study involving 33 women who developed severe PE or superimposed PE in the second trimester and were expectantly managed at a tertiary center. They were divided into groups with and without severe FGR on admission (severe FGR (+) group: 17 women; severe FGR (−) group: 16 women) for comparison of the duration of pregnancy prolongation, major maternal complications, and perinatal outcomes. The data are presented as medians (range) or frequencies (percentage).ResultsThe duration of pregnancy prolongation was 10 days in both groups. Major maternal complications occurred in 5 of 17 women (29.4%) in the severe FGR (+) and 5 of 16 (31.3%) in the severe FGR (−) group, showing very similar incidence rates in the 2 groups. The perinatal survival rates were favorable at 82.4% (14/17) in the severe FGR (+) and 100% (16/16) in the severe FGR (−) group.ConclusionRegarding expectant management of severe preeclampsia occurring in the second trimester, there was no difference in the duration of pregnancy prolongation between the groups with and without severe FGR on admission. Because favorable perinatal outcomes can be expected without compromising maternal safety by prolonging pregnancy as expectant management for severe FGR, it was suggested that women with severe FGR are suitable candidates for expectant management.     

Higher plasma AOPP is associated with increased proteinuria excretion and decreased glomerular filtration rate in pre-eclamptic women

BackgroundAdvanced oxidation protein products (AOPP) as a novel biomarker of oxidative stress has been demonstrated in chronic kidney disease (CKD) patients. The research was to investigate the plasma AOPP level in pre-eclamptic pregnant women and its correlation with 24-h proteinuria collection, cystatin C(CC), uric acid(UA) and creatinine(Cr).MethodsFifty pre-eclamptic women, including 22 mild and 28 severe preeclampsia were enrolled. Twentyfive healthy singleton pregnant women were selected as control. Blood samples were obtained from all groups to measure the levels of AOPP, CC, UA, Cr and other biochemical parameters at admission. Total protein in the 24 h urine collection was measured. Pearson correlation was performed to evaluate the associations between plasma AOPP level and 24-h proteinuria collection, plasma cystatin C, uric acid and creatinine.ResultsThe means of AOPP levels were significantly different among severe, mild pre-eclampsia and normotensive pregnant women (88.6 ± 10.0 μmmol/L, 72.1 ± 11.1 μmmol/L and 48.7 ± 11.3 μmmol/L). The means of cystatin C levels were significantly different among severe, mild pre-eclampsia and normotensive pregnant women (1.8 ± 0.6 μmmol/L, 1.2 ± 0.3 μmmol/L and 1.0 ± 0.2 μmmol/L). Mild, severe pre-eclampsia and control groups did not differ significantly from each other with respect to uric acid and creatinine. Significant positive correlation between AOPP and 24-h proteinuria excretion in preeclamptic pregnant women was found in mild and severe preeclamptic pregnant women (r = 0.792). Significant positive correlation between AOPP and cystatin C was found in normal and preeclamptic pregnant women (r = 0.521).ConclusionPlasma AOPP level had a significant positive correlation with 24-h proteinuria excretion and cystatin C. Further research about the relevance between the level of AOPP and the onset of preeclampsia was needed in order to have a profound prospective in oxidative stress and preeclampsia.     

Fetal DNA does not induce preeclampsia-like symptoms when delivered in late pregnancy in the mouse

IntroductionThe etiology of preeclampsia is unclear. Fetal DNA is present in higher concentrations in the plasma of pregnant women suffering from preeclampsia than in the plasma of healthy pregnant women. A previously published study has shown that human fetal DNA injected into pregnant mice induces preeclampsia-like symptoms when administered between gestation days 10–14. The aim of our experiment was to determine whether or not similar effects would be induced by administration of human and mouse fetal DNA, as well as mouse adult DNA and lipopolysaccharide during late pregnancy in the mouse.MethodsExperimental animals were injected daily intraperitoneally during gestation days 14–18 with either saline – negative control, lipopolysaccharide – positive control, or various types of DNA. On gestation day 19, blood pressure and proteinuria were measured, and placental and fetal weights were recorded.ResultsFetal and placental hypotrophy were induced only by lipopolysaccharide (p < 0.001). Neither fetal nor adult DNA induced changes in fetal/placental weight. None of the experimental groups had higher blood pressure or urinary protein in comparison to saline treated animals.DiscussionIn our experiment, we found that there was no effect from intraperitoneally injected human fetal DNA, mouse fetal DNA, or mouse adult DNA on pregnant mice. Additionally, relatively high doses of various types of DNA did not induce preeclampsia-like symptoms in mice when administered in late pregnancy. Our negative results support the hypothesis that the increase of fetal DNA circulating in maternal circulation during the third trimester is rather a consequence than a cause of preeclampsia.     

Association between polymorphisms in IL-27 gene and pre-eclampsia

Pre-eclampsia is a complex pregnancy-specific hypertensive syndrome, and it is a leading cause of maternal and neonatal death worldwide. We aimed to evaluate the associations between polymorphisms of IL-27 gene and pre-eclampsia susceptibility in Han Chinese women.Methods663 pregnant women were enrolled in a case-control study (212 cases and 451 normal pregnancies). The rs153109 and rs17855750 variants were discriminated using Polymerase Chain Reaction – Restriction Fragment Length Polymorphism (PCR–RFLP) methods.ResultsA significantly reduced risk of pre-eclampsia was observed in the rs153109 GG genotype compared with the AA or AA/AG genotypes (GG versus AA: OR = 0.51, 95%CI = 0.30–0.86; GG versus AA/AG: OR = 0.60, 95%CI = 0.37–0.98). Significantly reduced pre-eclampsia susceptibility was also associated with the AG/GG genotypes of rs153109 (OR = 0.68, 95%CI = 0.49–0.94) in dominant model. After stratification analysis, the different distribution of AG/GG genotypes was particular significant in the severe pre-eclampsia subgroup (OR = 0.65, 95%CI = 0.45–0.92) and the early-onset severe pre-eclampsia subgroup (OR = 0.51, 95%CI = 0.30–0.87). Additionally, significantly increased mild pre-eclampsia risk was observed associated with rs17855750 GT/GG and GT genotypes when compared with TT and TT/GG genotypes (GT/GG versus TT: OR = 2.27, 95%CI = 1.12–4.55; GT versus TT/GG: OR = 2.56, 95%CI = 1.28–5.26).ConclusionIt is biologically plausible that SNPs in IL-27 may have effect on individual susceptibility to pre-eclampsia. The results suggest the presence IL-27 rs153109, rs17855750 variants may be able to be used as markers for the genetic susceptibility to pre-eclampsia.     

Angiopoietin-2: A Promising Indicator for the Occurrence of Severe Preeclampsia

Background. The known connection between placental hypoxia and the development of preeclampsia suggests that angiogenic factors in the placenta would be changed and affect the maternal and/or umbilical cord plasma levels in patients with preeclampsia. Objective. The aim of this study was to determine the difference and correlation of placental mRNA expression and maternal/umbilical cord plasma concentrations of vascular endothelial growth factor A (VEGF-A), angiopoietin-1, and angiopoietin-2 between women with severe preeclampsia and normal pregnancies. Methods. Sixteen patients with severe preeclampsia and 29 normotensive pregnant women were studied. The placental mRNA expression was assessed using real-time quantitative RT-PCR analysis. Maternal/umbilical cord plasma levels were measured using an enzyme-linked immunoassay. Nonparametric methods were applied for statistical analysis. Results. Placental mRNA expression of angiopoietin-2 was significantly increased in patients with severe preeclampsia (p < 0.001). The maternal plasma angiopoietin-2 protein level was also significantly increased in women with severe preeclampsia (p < 0.05) and showed a positive correlation with the placental mRNA expression of angiopoietin-2 (r = 0.54, p < 0.005). For VEGF-A and angiopoietin-1, there were no significant differences between the two groups. A maternal plasma angiopoietin-2 concentration of 8.4 ng/mL had a sensitivity of 63% and a specificity of 83% for predicting severe preeclampsia. Conclusion. Placental angiopoietin-2 mRNA expression was increased and correlated with the maternal plasma angiopoietin-2 protein concentration in women with severe preeclampsia. This suggests that the plasma angiopoietin-2 protein level may be a candidate marker for severe preeclampsia.     

The Expression of Connective Tissue Growth Factor in Pregnancies Complicated by Severe Preeclampsia or Fetal Growth Restriction

We tested the hypothesis that the expression of placental connective tissue growth factor (CTGF) is enhanced in pregnancies complicated by severe preeclampsia (PE) or fetal growth restriction (FGR). CTGF expression was analyzed using immunostaining, western blot and real-time quantitative PCR in placental samples obtained after third trimester cesarean deliveries without labor from women with severe PE (n = 11), idiopathic FGR (n = 14), or healthy controls (n = 14). Serum CTGF concentrations were analyzed using ELISA. We found that CTGF was stably expressed in villous trophoblasts throughout pregnancy. The expression of CTGF mRNA in placentas from severe PE or FGR was higher than placentas from controls. Whereas the levels of placental CTGF protein were similar between normal and severe PE, maternal and fetal serum CTGF levels were elevated in severe PE. Maternal CTGF levels were also distinctively elevated in women with PE or FGR with histological evidence of placental injury. The enhancement of CTGF expression as well as serum CTGF levels in clinical conditions attributed to placental dysfunction suggests a role for this secretary protein in the pathophysiology of placental injury or its sequelae.     

Serum neprilysin levels are elevated in preeclampsia

ObjectiveTo evaluate the possible associations between serum Neprilysin (NEP) levels and preeclampsia and mild and severe preeclampsia subgroups.Materials and methodsFifty-five consecutive women with mild preeclampsia and fifty-five consecutive women with severe preeclampsia were compared with 110 approximately gestational age-matched (±1 week) women with an uncomplicated pregnancy.ResultsMean serum NEP was significantly higher in women with preeclampsia compared to that of the gestational age-matched-controls (231.62 ± 65.30 pg/mL vs. 187.75 ± 84.38 pg/mL, p < 0.001). Mean serum NEP was significantly higher in the mild preeclampsia group compared to its gestational age-matched control group (228.84 ± 67.26 pg/mL vs. 186.14 ± 85.09 pg/mL, p = 0.008); and in the severe preeclampsia group compared to its gestational age-matched control group (234.45 ± 63.85 pg/mL vs. 189.29 ± 84.59 pg/mL, p = 0.004). Serum NEP was positively correlated with systolic and diastolic blood pressure, BUN, uric acid, and creatinine.ConclusionMean serum NEP was significantly higher in women with preeclampsia than women with an uncomplicated pregnancy. Further studies are needed to elucidate the possible therapeutic role of NEP inhibitors to treat preeclampsia.     

Altered interleukin-6 receptor, IL-6R and gp130, production and expression and decreased SOCS-3 expression in placentas from women with pre-eclampsia

Interleukin-6 (IL-6) and its receptor complex, IL-6 receptor (IL-6R) and gp130, are critical in induction of suppressor of cytokine signalling-3 (SOCS-3) protein, a negative cytokine regulator and anti-inflammatory mediator, in a biological system. Increased inflammatory response is believed to contribute to the placental dysfunction in pre-eclampsia (PE). However, it is not known if altered IL-6 receptor signalling and decreased SOCS-3 expression occur in placentas from PE. To study this, we examined IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) production by villous tissue from normal and PE placentas. Hypoxia effects on IL-6, sIL-6R and sgp130 production was determined. IL-6R, gp130 and SOCS-3 expression were determined by immunohistochemical staining and by Western blot. Our results showed that under normoxic conditions (21% O₂), villous tissue from PE placentas produced relative more sgp130, but significantly less IL-6 and sIL-6R (p < 0.01) than normal placental tissue. The ratio of sgp130/sIL-6R release was significantly higher by PE placentas than normal placentas, p < 0.01. Under hypoxic conditions (2% O₂), IL-6 production was significantly reduced by both normal (p < 0.01) and PE (p < 0.05) placental tissue. Hypoxia promoted sgp130 release by normal, but not by PE, placental tissue. Reduced IL-6R and SOCS-3 immunostaining and expression were found in PE placentas. We concluded that increased ratio of sgp130/sIL-6R production and/or reduced sIL-6R production combined with down-regulation of IL-6R and SOCS-3 expression in trophoblasts may lead to less cytokine inhibitory activity in PE placentas, which may account for the increased placental inflammatory response in PE.