Decreased very-low-density lipoprotein and low-density lipoprotein receptor messenger ribonucleic acid expression in placentas from preeclamptic pregnancies

OBJECTIVE: Our purpose was to investigate the levels of very-low-density lipoprotein and low-density lipoprotein receptor messenger ribonucleic acid expression in placentas obtained from normal pregnant women at various gestational stages and from patients with preeclampsia. STUDY DESIGN: The relative level of expression of very-low-density lipoprotein and low-density lipoprotein receptor messenger ribonucleic acid in each sample was determined by Northern blot analysis as a ratio of the intensity to that of glyceraldehyde-3-phosphate dehydrogenase messenger ribonucleic acid. RESULTS: The expression of very-low-density lipoprotein receptor messenger ribonucleic acid increased significantly (p < 0.05) from both the first (n = 9) and second (n = 8) trimesters to the third (n = 11) trimester. Similarly, the expression of low-density lipoprotein receptor messenger ribonucleic acid increased significantly (p < 0.05) from the first to the third trimester. The expression of both very-low-density lipoprotein and low-density lipoprotein receptor messenger ribonucleic acids in third-trimester placentas from preeclamptic pregnancies (n = 13) was significantly lower than that in normal pregnancies in the third trimester. CONCLUSION: These results demonstrate the expression of very-low-density lipoprotein and low-density lipoprotein receptor messenger ribonucleic acids in the human placenta, both of which increase at late gestational stages, and the decreased expression in cases of preeclampsia. Abnormal fetomaternal lipid metabolism resulting from low expression of these receptors in the placenta may be involved in the pathogenesis of preeclampsia. (Am J Obstet Gynecol 1996;175:1551-6.)     

Increased Placental Telomerase mRNA in Hypertensive Disorders of Pregnancy

Objective.?We assessed hTERT mRNA levels in normal versus preeclamptic placental samples, examining hTERT expression levels in different clinical manifestations of hypertensive disorder of pregnancy.?Methods.?We performed a single-site, prospective case-control study of hTERT mRNA levels in placentas from term and preterm pregnancies with hypertensive disorders compared with unaffected pregnancies. Placental biopsies were collected from 61 patients (preeclamptic: 32; non-preeclamptic (control): 29). Total RNA from placenta was isolated and reversely transcribed to c‐DNA. A probe-specific real-time quantitative PCR assay was employed to determine the relative expressional levels of hTERT mRNA levels in these placentas from both unaffected and affected pregnancies with different categories of hypertensive disorders including preeclampsia, severe preeclampsia, eclampsia and HELLP syndrome (Hemolysis, Elevated Liver function tests, Low Platelet).?Results.?The average ratio of hTERT mRNA levels was 1.73 in the preeclamptic group and 1.02 for control group (p < 0.0001). The hTERT expression levels were elevated for each of the different categories of hypertensive disorders of pregnancy compared with control: HELLP syndrome 1.86, severe preeclampsia 1.81, eclampsia 1.71 and mild preeclampsia 1.63. In addition, hTERT levels were higher in severe than mild preeclampsia (p < 0.01). Conclusions.?Elevated hTERT mRNA expression is observed in placentas from pregnancies with different clinical manifestations of hypertensive disorders of pregnancy. The patho-physiological significance of this finding awaits further studies.     

The expression of heparanase in normal and preeclamptic placentas

Objective: Heparanase plays a central role in processes of placentation. Abnormal placentation may result in inadequate uteroplacental blood flow, leading to unsuccessful pregnancy outcome and preeclampsia. We aimed to evaluate heparanase expression in placentas of preeclamptic patients.

Materials and methods: Placental tissue samples were collected immediately after delivery from 9 preeclamptic patients and 3 healthy controls at term, and were analyzed by immunohistochemistry, western blot analysis and real-time PCR, with regard to the presence of heparanase

Results: Immunohistochemistry staining for heparanase did not differ between normal and preeclamptic placental sections. On the other hand, western blot analysis revealed increased expression of heparanase in preeclpamptic placentas compared to controls, p?=?0.001. Similarly, RT-PCR analysis showed also an increased expression of heparanase m-RNA compared to health controls, p?=?0.005.

Conclusion: Heparanase is over expressed in preeclamptic placentas compared to normal healthy controls, suggesting its role in the development of preeclampsia.     

Differential expression of human placental PAPP-A2 over gestation and in preeclampsia

IntroductionPregnancy Associated Plasma Protein A2 (PAPP-A2) is a pregnancy related insulin-like growth factor binding protein-5 (IGFBP-5) protease, known to be elevated in preeclampsia. As the insulin-like growth factors are important in human implantation and placentation, we sought to determine the expression pattern of PAPP-A2 over human gestation in normal and preeclamptic pregnancies to evaluate its role in placental development and the pathogenesis of preeclampsia.MethodsPlacental basal plate and chorionic villi samples, maternal and fetal cord blood sera were obtained from preeclamptic and control pregnancies. Formalin-fixed tissue sections from across gestation were stained for cytokeratin-7, HLA-G, and PAPP-A2. PAPP-A2 immunoblot analysis was also performed on protein lysates and sera.ResultsPAPP-A2 expression is predominately expressed by differentiated trophoblasts and fetal endothelium. Chorionic villi show strong expression in the first trimester, followed by a progressive decrease in the second trimester, which returns in the third trimester. PAPP-A2 expression is not impacted by labor. PAPP-A2 is increased in the basal plate, chorionic villi and maternal sera in preeclampsia compared to controls, but is not detectable in cord blood.DiscussionPAPP-A2 is differentially expressed in different trophoblast populations and shows strong down regulation in the mid second trimester in chorionic villous samples. Both maternal sera and placental tissue from pregnancies complicated by preeclampsia show increased levels of PAPP-A2. PAPP-A2 levels are not altered by labor. Additionally, PAPP-A2 cannot be detected in cord blood demonstrating that the alterations in maternal and placental PAPP-A2 are not recapitulated in the fetal circulation.     

人类白细胞相关抗原-G及其各亚型mRNA在正常妊娠及重度子前期患者胎盘组织中的表达

目的研究人类白细胞相关抗原-G(HLA-G)及其各个亚型mRNA在正常妊娠及重度子前期患者胎盘组织中的表达。方法选取2005-01-2005-06第四军医大学唐都医院10例重度子前期患者(研究组)及10例正常妊娠胎盘组织(对照组),应用荧光定量RT-PCR比较两组间HLA-G及其各个亚型mRNA(HLA-G1、G2、G3、G4、G5、G6)的表达。结果与对照组相比,重度子前期患者胎盘组织中总HLA-GmRNA显著降低,以HLA-G1、HLA-G3降低为主,差异有统计学意义(P<0.05)。结论HLA-G1与HLA-G3在胎盘组织中的低表达可能与妊娠期高血压疾病的发病和病理生理过程有关。     

Low plasma levels of decoy receptor 3 (DcR3) in the third trimester of pregnancy with preeclampsia

ObjectiveThe pathophysiology of preeclampsia, a major threat during pregnancy characterized by excessive inflammatory status, remains unclear. Decoy receptor 3 (DcR3), a soluble member of the tumor necrosis factor receptor (TNFR) superfamily, is capable of inducing anti-apoptosis via binding with TL1A and anti-inflammation by driving Th2 immune reactions. DcR3 may, therefore, play a role in immune modulation during pregnancy. The purpose of this study is to explore the role of DcR3 in normal and preeclamptic pregnancies.Materials and methodsPlasma samples from 104 normal pregnant women (26, 42, and 36 in the first, second, and third trimester, respectively) and 10 patients with preeclampsia in the third trimester were collected. Plasma DcR3 levels were determined by using commercial ELISA kits. ANOVA and linear regression analysis were performed to analyze the relationship between gestational age and DcR3 levels. After adjusting for gestational days, the levels of plasma DcR3 in preeclamptic and non-preeclamptic women in the third trimester were compared.ResultsThe plasma levels of DcR3 gradually decreased as the gestational days increased during pregnancy (p < 0.05). In the third trimester, pregnant women with preeclampsia had significantly lower plasma DcR3 levels compared to non-preeclamptic women (p < 0.05).ConclusionsWe found that plasma DcR3 levels gradually decreased as gestation progressed. The levels of plasma DcR3 in preeclamptic women were significantly lower than those of normal pregnant women, suggesting that a potential involvement of DcR3 in normal pregnancy and decreased levels of DcR3 may be related to preeclampsia.     

Association of Maternal Serum CRP,IL-6, TNF-α, Homocysteine,Folic Acid and Vitamin B12 Levels with the Severity of Preeclampsia and Fetal Birth Weight

Objective: To assess the levels and clinical significance of high sensitive(hs)-CRP (C‐reactive protein), IL-6(interleukin-6), TNF-α(tumor necrosis factor-α), homocysteine, folic acid and vitamin B12 in normotensive healthy pregnant women, mild and severe preeclamptic patients, and to evaluate the correlations between these markers and the severity of preeclampsia and fetal birth weight. Study design: Using a cross-sectional study design, hs-CRP, IL-6, TNF-α, homocysteine and vitamin B12 were measured in the third trimester of pregnancy from normotensive healthy women with uncomplicated pregnancies (n = 62), mild (n = 61) and severe (n = 60) preeclamptic patients. Results: There were statistically significant differences between three groups for hs-CRP (p = 0.012), TNF- α (p = 0.046), IL-6 (p = 0.015), homocysteine (p < 0.001) and fetal birth weight (p < 0.001). Fetal birth weights in mild (2477 ± 746) and severe (2435 ± 768) preeclamptic patients were significantly lower than controls (3485 ± 365) (p < 0.001). No significant difference was found between the three groups for folic acid (p = 0.066) and vitamin B12 (p = 0.286). Bonferroni adjusted multiple comparison test showed that the statistical differences with respect to TNF-α, IL-6 and homocysteine were mainly created by control and severe preeclampsia groups. Hs-CRP levels still remained higher in severe preeclampsia patients than mild preeclampsia and normotensive patients except for overweight patients in the previous two groups after Bonferroni post hoc adjustment test. Conclusion: Elevated maternal serum levels of hs-CRP, TNF- α, IL-6 and homocysteine in preeclamptic women correlate with fetal birth weight in the early third trimester.     

The surface expression of HLA-F on decidual trophoblasts increases from mid to term gestation

HLA-F has recently only begun to be studied in earnest, and has been thought not to be expressed on the cell surface. However, in our previous report, we demonstrated surface expression of HLA-F on extravillous trophoblasts (EVTs) invading the decidua in term placental tissues. To better understand its function, we attempted to determine when surface expression of HLA-F begins during normal pregnancy, and whether there is a difference in expression between normal and preeclamptic placentas, by comparing the expression of HLA-G and -E by immunohistochemical staining with anti-HLA-E, -F and -G antibodies (3D12, 3D11 and 87G, respectively). In EVTs, HLA-F was expressed only in the cytoplasm weakly during the first trimester, after which expression increased and moved to the cell surface with the progression of pregnancy from the second trimester, which was confirmed by the results of double-labeled immunofluorescence staining with anti-HLA-F and anti-HLA-G antibodies, and by flow cytometry using trophoblasts isolated from the decidua. HLA-E showed similar expression as HLA-F, though it was expressed on the cell surface from the first trimester, while HLA-G was expressed strongly in the cytoplasm and on the cell surface during all stages of pregnancy. The expressions of HLA-E, -F and -G in preeclamptic placentas were not different from those in normal placentas, though there were a greater number of necrotic EVTs in preeclampsia. The increase in expression of HLA-E and HLA-F from the second trimester to full term was coincident with the timing of rapid growth of the fetus. Our results suggest that these may function together to prepare an environment that supports fetal growth.     

Alteration of vascularization in preeclamptic placentas measured by three-dimensional power Doppler ultrasound

Abstract

Objective: To evaluate the alteration of vascularization in preeclamptic placentas measured by three-dimensional (3D) power Doppler ultrasound.

Methods: We performed a prospective study of placental vascularization and placental volume in 27 singleton pregnancies complicated by preeclampsia and 41 normal pregnancies from 27 to 39 weeks of gestation. The placental volume was analyzed using the VOCAL imaging analysis program and 3D power histogram was used to calculate the placental vascular indices including vascularization index (VI), flow index (FI) and vascularization flow index (VFI).

Results: Of the 27 preeclamptic pregnancies, 9 were complicated by intrauterine growth restriction and 15 were severe preeclampsia. Furthermore, nine of the preeclamptic pregnancies had abnormal end diastolic flow in the umbilical artery. No significant correlation was noted between the placental vascular indices and gestational age in normal pregnancies. The placental vascular indices including VI, FI and VFI were significantly lower in preeclamptic placentas compared with controls (VI, p?<?0.001; FI, p?=?0.022; VFI, p?<?0.001). Preeclamptic placental volume was also decreased compared with that of the controls (p?=?0.002). After adjustment for confounding factors, significant differences were observed in VI and placental volume. However, no correlation was found between 3D power Doppler vascular indices and umbilical artery flow velocities, and neither intrauterine growth restriction nor the severity of preeclampsia could be predicted by the vascular indices.

Conclusion: VI and placental volume are reduced in preeclamptic placenta. Placental vascular indices using 3D power Doppler ultrasound provide insights of placental vascularization in preeclampsia.     

人白细胞抗原-G mRNA各亚型在重度子(癎)前期胎盘组织中的表达

目的　探讨人白细胞抗原-G(human leukocyte antigen-G,HLA-G)各亚型在早发型、晚发型重度子(癎)前期患者以及正常妊娠产妇胎盘组织中表达的差异. 方法　使用巢式RT-PCR方法检测11例早发型重度子(癎)前期患者、14例晚发型重度子(癎)前期患者以及8例正常分娩产妇胎盘组织中HLA-G各亚型mRNA表达的差异情况. 结果 与正常对照组相比,HLA-G1亚型在早发型和晚发型重度子(癎)前期患者的胎盘组织中表达明显减少(中位数:早发型组1.37,P<0.05;晚发型组24.90,P<0.05;正常对照组46.67,P<0.05).HLA-G2亚型在晚发型重度子(癎)前期患者的胎盘组织中表达水平较高(中位数:早发型组0;晚发型组21.59,P<0.05;正常对照组5.39).HLA-G5亚型在早发型以及晚发型重度子(癎)前期患者的胎盘组织中表达水平增高(中位数:早发型组19.23;晚发型组3.65;正常对照组1.33). 结论 HLA-G膜结合型亚型mRNA在胎盘组织中表达减少以及HLA-G可溶性亚型mRNA在胎盘组织中表达的增高,可能在子(癎)前期的发病机制中起到一定的作用.     

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 levels of interleukin-6, interleukin-1β and human chorionic gonadotropin in pre-eclamptic and normal pregnancy

Studies in placentas from the first trimester and in vitro models indicate that interleukin (IL)-1β and IL-6 induce the release of human chorionic gonadotropin (hCG). During pre-eclampsia there is an increase of pro-inflammatory cytokines; however, its relationship with hCG levels during the third trimester of pregnancy has not been determined. The aim of the present study was to evaluate the relationship between blood levels of IL-6, IL-1β and hCG in normal pregnancy and pre-eclampsia. Blood samples during the third trimester of pregnancy from women with severe pre-eclampsia (n = 20) or normal pregnancy (n = 20) were assayed for hCG by immunoassay, IL-6 and IL-1β by enzyme-linked immunosorbent assay. Serum level of IL-6 was significantly higher in pre-eclamptic than in normal women (16.5 ± 2.1 vs. 4.9 ± 1.1 pg/ml); however, IL-1β was similar in both groups. Although hCG was higher in pre-eclampsia than normal pregnancy, the difference was not statistically significant. Furthermore, IL-1β in normal pregnancy was correlated negatively with hCG (r = ?0.69, p < 0.001). In conclusion, serum levels of IL-6 were increased in pre-eclampsia but were not correlated with hCG or IL-1β; however, in normal pregnancy there was a negative correlation between IL-1β and hCG. The interaction between IL-1β and hCG at the third trimester needs to be investigated.     

Plasma and tissue expression of the long pentraxin 3 during normal pregnancy and preeclampsia

OBJECTIVE: Cell death normally occurs during pregnancy and is critical during its common complication, preeclampsia. The long pentraxin 3 (PTX3) gene is generated in tissues that cope with excessive or deregulated cell death and inhibits the cross-presentation of cell-associated antigens. We examined whether PTX3 is expressed during pregnancy and possibly involved in the development of preeclampsia. METHODS: Women with preeclampsia (n = 30), women with uncomplicated pregnancies (n = 66), age-matched healthy women (n = 50), women who developed acute bacterial infections (n = 20), and women with rheumatoid arthritis (n = 20) were studied. The concentrations of PTX3 were measured in the blood by a sandwich enzyme-linked immunosorbent assay (ELISA) and in placentas by immunohistochemistry. The concentrations of PTX3 and C-reactive protein in the various groups were compared by nonparametric tests (the Mann-Whitney U and the Kruskal-Wallis tests). The odds of developing preeclampsia were assessed using logistic regression. RESULTS: PTX3 was expressed in amniotic epithelium and chorionic mesoderm, trophoblast terminal villi, and perivascular stroma in placentas from pregnancies of uncomplicated subjects. Circulating levels steadily rose during normal gestation and peaked during labor. Serum levels of PTX3 were strikingly higher in preeclampsia compared with normal control pregnancies (5.08 +/- 1.34 and 0.59 +/- 0.07 ng/mL, respectively, P < .001). Sites of higher expression in the placentas from preeclamptic patients include infarcts and fibrinoid zones. CONCLUSION: Defects in the homeostatic response to cell death/remodeling events, revealed by enhanced levels of PTX3, could be implicated in preeclampsia. LEVEL OF EVIDENCE: II-2.     

Levels of asymmetric dimethylarginine throughout normal pregnancy and in pregnancies complicated with preeclampsia or had a small for gestational age baby

Objective: The aim of this study was to investigate maternal asymmetric dimethylarginine (ADMA) concentrations at the three trimesters of pregnancy in uncomplicated pregnancies and in women who developed preeclampsia or had small for gestational age infants (SGA) without preeclampsia. Methods: ADMA concentrations were retrospectively determined in the first, second and third trimester of pregnancy in 41 uncomplicated pregnancies, 10 pregnancies complicated with preeclampsia and 14 pregnancies that delivered a SGA baby. ADMA was measured with an ELISA kit. Results: Mean (±SD) concentrations of ADMA (µmol/L) in uncomplicated l pregnancies were: 0.51?±?0.14; 0.52?±?0.13; 0.58?±?0.16 in the three trimesters, respectively. ADMA concentrations in SGA pregnancies were significantly lower in each trimester compared to uncomplicated pregnancies: (0.40?±?0.10, p?=?0.005 1st trim; 0.42?±?0.10, p?=?0.007 2nd trim; 0.45?±?0.10, p?=?0.007 3rd trim). Although pregnancies that developed preeclampsia had higher ADMA concentration in all trimesters compared to uncomplicated pregnancies (0.58?±?0.10; 0.63?±?0.14; 0.68?±?0.11), the difference was statistically significant only in the 2nd trimester (p?=?0.02). Conclusions: Maternal serum ADMA concentration tends to increase during normal pregnancy. Pregnancies with SGA infants had significantly lower ADMA levels in all trimesters of pregnancy. ADMA concentrations in the 2nd trimester was significantly elevated in pregnancies that later developed preeclampsia.     

Wnt5a inhibited human trophoblast cell line HTR8/SVneo invasion: implications for early placentation and preeclampsia

Objective: Wnt5a and Wnt signaling play potential roles in human placental and fetal development. The objective of this study is to explore the role of Wnt5a in the invasion of the human trophoblast cell line HTR8/SVneo and the probable mechanism of early placentation and preeclampsia in which Wnt5a is involved.

Methods: Human first trimester villous tissues from normal pregnancies and third trimester placentas from pregnancies with or without preeclampsia (PE) were used in the detection of the expression and subcellular location of Wnt5a. The human trophoblast cell line HTR8/SVneo was treated with 0–400?ng/ml recombinant Wnt5a to investigate the role of Wnt5a in human trophoblast invasion.

Results: Human first trimester villous is accompanied by the decreased expression of Wnt5a compared with term placenta. Upregulated Wnt5a was detected in PE placenta compared with the normal control. Wnt5a inhibited the migration and invasion of HTR8/SVneo cells with decreased integrin β1, α5 and N-cadherin. Moreover, Wnt5a downregulated β-catenin in HTR8/SVneo cells.

Conclusions: These findings strongly suggest that Wnt5a inhibits the invasion of HTR8/SVneo cells. Decreased Wnt5a facilitates early placentation, whereas increased Wnt5a contributes to the pathogenesis of PE with insufficient trophoblast invasion. Aberrant Wnt5a may function by impairing Wnt non-canonical/β-catenin signaling pathway in trophoblasts.     

Reduced expression of survivin, the inhibitor of apoptosis protein correlates with severity of preeclampsia

Introduction

Preeclampsia is a major complication of pregnancy affecting maternal and fetal health. Although the pathogenesis of preeclampsia is unclear, it is believed that trophoblast apoptosis plays an important role in the pathogenesis of preeclampsia during pregnancy. Survivin is a member of the inhibitor of apoptosis protein family that uniquely promotes trophoblast proliferation. In this study we investigated the alteration of survivin levels during pregnancy and compared the survivin protein and mRNA between preeclampsia and normal pregnancy.

Methods

The mRNA level of survivin in first, second and third trimester placentae was measured by Real-time PCR. The expression of survivin in preeclamptic placentae (including severe and mild preeclampsia) and in age-matched normal placentae was measured by immunohistochemistry. The mRNA levels of survivin in preeclamptic or normal placentae were measured by Real-time PCR.

Results

The mRNA level of survivin was significantly reduced throughout gestation. The mRNA level of survivin in preeclamptic placentae was significantly reduced compared to that in normal placenta. The mRNA level of survivin in severe preeclamptic placentae was further significantly reduced compared to that in mild preeclamptic placentae. In addition, survivin was expressed on syncytiotrophoblasts and cytotrophoblasts and the expression of survivin was significantly decreased in preeclamptic placenta compared to that in normal placenta (p = 0.01). Furthermore the expression of survivin in severe preeclamptic placentae was significantly lower than that in mild preeclamptic placentae.

Conclusion

Our current data suggests lower placental expression of survivin may be associated with the severity of preeclampsia.     

Immunocytochemical Localization of Endothelin-1 in Human Placenta from Normal and Preeclamptic Pregnancies

Objective. The aim of this study was to examine the distribution of endothelin-1 (ET-1) in the human placenta at different gestational ages and to determine whether differences in ET-1 immunoreactivity occurred in preeclamptic compared with uncomplicated pregnancies.

Methods. Localization of ET-1 was investigated by the immunoperoxidase technique in first-trimester, second-trimester, and term human placentas from normal pregnancies and in placentas from preeclamptic pregnancies.

Results. In normal placentas from all gestational ages studied, endothelin-1 immunoreactivity (ET-1 IR) was specifically detected in the endothelium of the fetal vessels and in the syncytiotrophoblast. ET-1 IR was also expressed by the villous cytotrophoblast of first- and second-trimester normal placentas. The extravillous cytotrophoblast of the basal and chorionic plates also exhibited ET-1 IR, but with varying degrees of intensity. In preeclamptic placentas, the expression of ET-1 IR was uneven with a negative staining in all placentas from pregnancies between the 29th and 32nd weeks of gestation. The expression of ET-1 IR was most intense in some syncytiotrophoblast tissue in the terminal villi after the 33rd week of gestation. In placentas from preeclamptic pregnancies between the 35th and the 36th weeks of gestation, strong ET-1 IR expression was evident in the endothelium of fetal vessels and in the syncytiotrophoblast. Regardless of gestational age, ET-1 IR was also observed in the extravillous cytotrophoblast of the basal and chorionic plates of preeclamptic placentas.

Conclusion. This study demonstrates that ET-1 IR is widely distributed in the human placenta and provides further evidence to support the concept that ET-1 plays an important role as a modulator of vascular tone in the uteroplacental and fetoplacental units and may participate in the pathogenesis of preeclampsia.     

ADAM17 regulates TNFα production by placental trophoblasts

Increased trophoblast TNFα production is an important component of placental dysfunction in preeclampsia. However, the mechanism of increased TNFα production in the preeclamptic placenta is largely unknown. ADAM17 is a metallopeptidase that functions as a TNFα converting enzyme. In this study, we examined ADAM17 expression in placentas from normal and preeclamptic pregnancies and found increased ADAM17 expression in preeclamptic placentas compared to those from normal placentas, p < 0.05. Since hypoxia/oxidative stress is an underlying pathophysiology in the preeclamptic placenta, we further determined if hypoxia/oxidative stress could modulate ADAM17 expression and subsequently induce TNFα production in placental trophoblasts. Trophoblasts were isolated from normal term placentas and treated with cobalt (II) chloride (CoCl₂), a hypoxia mimetic agent, at different concentrations. Our results showed that CoCl₂ induced a dose-dependent increase in TNFα production that is associated with enhanced ADAM17 expression. Trophoblast expressions of HO-1 (a sensor of cellular oxidative stress) and caspase-3 (an indicator of apoptosis) in response to CoCl₂ stimulation were also examined. We further found that metallopeptidase inhibitor GM6001 and ADAM17 siRNA could block CoCl₂ induced TNFα production, demonstrating the role of ADAM17 in TNFα production in placental trophoblasts. These results suggest that oxidative stress-induced increased ADAM17 expression could contribute to the increased TNFα production in preeclamptic placentas.     

Fibronectin is a Marker for Organ Involvement and may Reflect the Severity of Preeclampsia

Objective. We have studied whether plasma fibronectin is related to a rise in blood pressure during normal pregnancy, whether it can be used for the early prediction of preeclampsia, and whether plasma fibronectin is a marker for organ involvement in preeclampsia.

Study design. Two hundred twenty-eight healthy pregnant nullipara women were examined prospectively during pregnancy. Analyses of fibronectin in plasma were performed in pregnancy weeks 16, 24, 28, 32, and 36. During the same period, 177 patients with suspected preeclampsia and/or intrauterine growth retardation (IUGR) were tested for plasma fibronectin, mainly in the third trimester.

Results. In the normal population of pregnant women (n=222/228), fibronectin levels were 0.35 ± 0.06 g/L in pregnancy week 16 and 0.43 ±0.12 g/L in week 36. These levels showed a positive correlation to blood pressure elevation during pregnancy (r=0.21, p=0.006). The six patients in this group (n=6/228) who later developed preeclampsia had higher fibronectin values 0.42 ± 0.07 g/L already in week 16 (p=0.023). In the population of women with suspected preeclampsia (preeclampsia, n=129; IUGR alone, n=17; hypertension or proteinuria during pregnancy, n=31), fibronectin values were significantly higher, 0.75 ± 0.27 g/L than in the normal population. Patients with preeclampsia and laboratory signs of organ involvement (n=56) showed significantly higher fibronectin values (0.85 ± 0.27 g/L) compared to preeclampsia without organ involvement (n=73) [0.76 ± 0.22 g/L (p=0.03)].

Conclusion. Our data show that fibronectin is related to blood pressure in pregnancy. Fibronectin values in women who develop preeclampsia are elevated already in pregnancy week 16 and were higher in those with laboratory signs of organ involvement.