Increased expression of vascular endothelial growth factor in placentas of p57(Kip2) null embryos

Placentas of mice lacking p57(Kip2) expression have trophoblastic hyperplasia. To elucidate the mechanism underlying this phenomenon, we studied expression of two angiogenic factors, vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). Immunohistochemical analysis with anti-VEGF antibodies indicated that VEGF expression was stronger and more clearly detectable in placentas of p57(Kip2) null embryos compared to wild-type placentas. PlGF showed no significant differences between placentas of p57(Kip2) null and wild-type embryos. In quantitative analysis, placentas of p57(Kip2) null embryos showed higher VEGF messenger (m)RNA and protein levels than did wild-type placentas. PlGF mRNA and protein levels were not significantly different. These findings suggest that VEGF is involved in the hyperplasia that occurs in placentas of p57(Kip2) null embryos.     

Interplay between HTRA1 and classical signalling pathways in organogenesis and diseases

The high temperature requirement factor A1 (HTRA1) is a serine protease which modulates an array of signalling pathways driving basal biological processes. HTRA1 plays a significant role in cell proliferation, migration and fate determination, in addition to controlling protein aggregates through refolding, translocation or degradation. The mutation of HTRA1 has been implicated in a plethora of disorders and this has also led to its growing interest as drug therapy target. This review details the involvement of HTRA1 in certain signalling pathways, namely the transforming growth factor beta (TGF-β), canonical Wingless/Integrated (WNT) and NOTCH signalling pathways during organogenesis and various disease pathogenesis such as preeclampsia, age-related macular degeneration (AMD), small vessel disease and cancer. We have also explored possible avenues of exploiting the serine proteases for therapeutic management of these disorders.     

IL-4 和IFN-γ mRNA 在子痫前期患者胎盘组织中的表达及意义

目的:检测胎盘组织中IFN-γ和IL-4的表达,探讨IFN-γ和IL-4在子痫前期的发病中的作用.方法:采用原位杂交法检测了20例正常妊娠孕妇和34例子痫前期组(包括16例轻度和18例重度)中的IFN-γ、IL-4 mRNA的表达水平,并通过图像分析系统对染色结果进行定量分析.结果:(1)IL-4 mRNA的表达在正常妊娠组、子痫前期轻度组和子痫前期重度组的表达无差异(P＞0.05).(2)与正常妊娠组、子痫前期轻度组相比,子痫前期重度组IFN-γ mRNA的表达有差异性(P＜0.05);子痫前期轻度组与正常妊娠组相比无差异(P＞0.05).(3)与正常妊娠组相比,子痫前期轻度组、重度组IFN-γ mRNA/IL-4 mRNA的比值均有差异性(P＜0.05),且随病情的加重比值增大.结论:Th1/Th2细胞因子的平衡偏离可能是导致子痫前期发病的病因之一.     

Chronotherapy With Low-Dose Aspirin for Prevention of Complications in Pregnancy

Preeclampsia and gestational hypertension are major contributors to perinatal morbidity and mortality. Several studies aimed to test the effects of low-dose aspirin (ASA) in the prevention of preeclampsia concluded that the beneficial effects of such treatment outweigh adverse ones. Such benefits have not been fully corroborated by larger randomized trials usually carried out in low-risk women, testing a dose of 60?mg/d ASA presumably ingested in the morning, and including women randomized as late as at 26–32 wks of gestation. The authors conducted a prospective, randomized, double-blind, placebo-controlled, chronotherapy trial on 350 high-risk pregnant women (183 nulliparous), 30.7?±?5.3 (mean?±?SD) yrs of age, and 13.5?±?1.4 wks of gestation at the time of recruitment. Women were randomly assigned to one of six groups, defined according to treatment (placebo or ASA, 100?mg/d) and time of treatment: upon awakening, 8?h after awakening, or at bedtime. Intervention started at 12–16 wks of gestation and continued until delivery. Blood pressure (BP) was measured by ambulatory monitoring (ABPM) for 48-h at baseline, every 4 wks until the 7th month of gestation, every 2 wks thereafter until delivery, and at puerperium. The effects of ASA on ambulatory BP were markedly dependent on administration time: there was no effect on BP, compared with placebo, when ASA was ingested upon awakening, but the BP reduction was highly statistically significant when low-dose ASA was ingested 8?h after awakening and, to a greater extent, at bedtime (p?<?.001). At puerperium, 6–8 wks after discontinuation of treatment, there was no statistically significant difference in 24-h BP means between the groups of women who ingested ASA at different circadian times. Women ingesting low-dose ASA, compared with placebo, evidenced a significantly lower hazard ratio (HR) of serious adverse outcomes, a composite of preeclampsia, preterm delivery, intrauterine growth retardation (IUGR), and stillbirth (.35, 95% confidence interval [CI]: .22–.56; p?<?.001). The HR of individual outcome variables, i.e., preeclampsia, preterm delivery, IUGR, and gestational hypertension, were also significantly lower with ASA versus placebo (p always?<?.041). There were small and nonsignificant differences in outcomes between placebo and low-dose ASA ingested upon awakening. These four groups combined showed highly significant greater event rate of serious adverse outcomes than women ingesting ASA either in the evening or at bedtime (HR: .19, 95% CI: .10–.39; p?<?.001). There was no increased risk of hemorrhage, either before or after delivery, with low-dose ASA relative to placebo (HR: .57, 95% CI: .25–1.33; p =?.194). Results indicate that (i) 100?mg/d ASA should be the recommended minimum dose for prevention of complications in pregnancy; (ii) ingestion of low-dose ASA should start at ≤16 wks of gestation; and (iii) low-dose ASA ingested at bedtime, but not upon awakening, significantly regulates ambulatory BP and reduces the incidence of preeclampsia, gestational hypertension, preterm delivery, and IUGR. ABPM evaluation at the first trimester of pregnancy provides sensitive endpoints for identification of women at high risk for preeclampsia who might benefit most from the cost-effective preventive intervention with timed low-dose ASA. (Author correspondence: rhermida@uvigo.es)     

Ambulatory Blood Pressure Monitoring for the Early Identification of Hypertension in Pregnancy

Gestational hypertension and preeclampsia are major contributors to perinatal morbidity and mortality. The diagnosis of gestational hypertension still relies on conventional clinic blood pressure (BP) measurements and thresholds of ≥140/90?mm Hg for systolic (SBP)/diastolic (DBP) BP. However, the correlation between BP level and target organ damage, cardiovascular disease risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinic BP measurement. Accordingly, ABPM has been suggested as the logical approach to overcoming the low sensitivity and specificity of clinic BP measurements in pregnancy. With the use of ABPM, differing predictable BP patterns throughout gestation have been identified for clinically healthy and hypertensive pregnant women. In normotensive pregnancies, BP steadily decreases up to the middle of gestation and then increases up to the day of delivery. In contrast, women who develop gestational hypertension or preeclampsia show stable BP during the first half of pregnancy and a continuous linear BP increase thereafter until delivery. Epidemiologic studies have also consistently reported sex differences in the 24-h patterns of ambulatory BP and heart rate. Typically, men exhibit a lower heart rate and higher BP than women, the differences being larger for SBP than DBP. Additionally, as early as in the first trimester of gestation, statistically significant increased 24-h SBP and DBP means characterize women complicated with gestational hypertension or preeclampsia compared with women with uncomplicated pregnancies. However, the normally lower BP in nongravid women as compared with men, additional decrease in BP during the second trimester of gestation in normotensive but not in hypertensive pregnant women, and significant differences in the 24-h BP pattern between healthy and complicated pregnancies at all gestational ages have not been taken into consideration when establishing reference BP thresholds for the diagnosis of hypertension in pregnancy. Several studies reported that use of the 24-h BP mean is not a proper test for an individualized early diagnosis of hypertension in pregnancy defined on the basis of cuff BP measurements, thus concluding that from such an awkward approach ABPM is not useful in pregnancy. The 24-h BP pattern that characterizes healthy pregnant women at all gestational ages suggests the use for diagnosis of a time-specified reference limit reflecting that mostly predictable BP variability. Once the time-varying threshold, given, for instance, by the upper limit of a tolerance interval, is available, the hyperbaric index (HBI), as a determinant of BP excess, can be calculated as the total area of any given subject's BP above the threshold. This tolerance-hyperbaric test, where diagnosis of gestational hypertension is based on the HBI calculated with reference to a time-specified tolerance limit, has been shown to provide high sensitivity and specificity for the early identification of subsequent hypertension in pregnancy, as well as a valuable approach for prediction of pregnancy outcome. ABPM during gestation, starting preferably at the time of the first obstetric check-up following positive confirmation of pregnancy, provides sensitive endpoints for use in early risk assessment and guide for establishing prophylactic or therapeutic intervention, and should thus be regarded as the required standard for the diagnosis of hypertension in pregnancy. (Author correspondence: rhermida@uvigo.es)     

血脂代谢指标及血清维生素A、E水平与子痫前期的相关性分析

目的:探讨血脂代谢指标及血清维生素A、E水平与子痫前期的相关性。方法:选取2016年12月至2017年12月期间来我院产检及住院分娩的722例妊娠妇女,选取94例子痫前期的妊娠妇女作为A组,其中轻度子痫前期32例作为A1组,重度子痫前期62例作为A2组,并从剩余的628例正常妊娠者中选取126例自愿参与本研究的妊娠妇女作为B组。收集并记录妊娠妇女的临床指标,包括入院时的孕周、孕次、产次、流产次数、血脂代谢指标、血清维生素A、E水平,分析血脂代谢指标、血清维生素A、E水平与子痫前期的相关性。结果:三组孕妇总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、载脂蛋白A(ApoA)、载脂蛋白B(ApoB)、维生素A、维生素E水平整体比较差异均具有统计学意义(均P0.05);A1组、A2组的TC、TG、LDL、HDL、ApoA、ApoB、维生素A、维生素E水平与B组比较,差异均有统计学意义(均P0.05),A2组TG、LDL高于A1组,而维生素A、维生素E水平低于A1组,差异均有统计学意义(均P0.05),Spearman秩相关分析结果显示,TC、TG、LDL、ApoB水平与子痫前期呈正相关(r=0.214,0.432,0.517,0.226,P=0.012,0.008,0.005,0.012),HDL、ApoA、维生素A、维生素E水平与子痫前期呈负相关(r=-0.282,-0.357,-0.539,-1.217,P=0.010,0.009,0.003,0.000)。结论:血脂代谢指标、维生素A、维生素E水平在子痫前期孕妇中表达异常,且这些指标与子痫前期密切相关,应重视妊娠期孕妇的血脂代谢指标、维生素A、维生素E水平的监测,并控制其水平,从而有效防治子痫前期。     

Altered Bcl-2 and Bax expression is associated with cultured first trimester human cytotrophoblasts apoptosis induced by hypoxia

Preeclampsia is associated with placental hypoxia at early gestation. We therefore investigated the effect of hypoxia on the apoptosis of cultured first trimester human cytotrophoblasts and the expression of apoptosis relevant proteins, Bcl-2 and Bax. First trimester human cytotrophoblasts were isolated and cultured under either standard or hypoxic conditions. Cellular apoptosis was monitored by TUNEL and Annexin V binding, and the expression of Bcl-2 and Bax was determined by Western blot analysis. Apoptosis increased significantly in cytotrophoblasts cultured for 24 h under hypoxic conditions in contrast with those cultured under standard conditions, meanwhile expression of Bcl-2 reduced, and that of Bax increased. These changes suggested that hypoxia induced apoptosis in cultured first trimester cytotrophoblasts with altered Bcl-2 and Bax expression. Further study is needed to explore the role of cytotrophoblasts apoptosis in hypoxia-induced maternal and fetal diseases.     

Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype

Cytotrophoblasts of the anchoring villi convert during human placentation from a transporting epithelium to an invasive, extravillous phenotype that expresses a distinct repertoire of adhesion molecules. Developing extravillous trophoblasts accumulate heparin-binding EGF-like growth factor (HB-EGF), a multifunctional cytokine, which binds HER1 and HER4 of the human EGF receptor (HER/ErbB) family. HB-EGF is downregulated in placentae of women with preeclampsia, a disorder associated with deficient trophoblast invasion, raising important questions about its physiological impact on cytotrophoblasts. Addition of HB-EGF during explant culture of first-trimester chorionic villi enhanced extravillous trophoblast differentiation and invasive activity. Using a first-trimester human cytotrophoblast line, the potential for autocrine and paracrine regulation of the developing trophoblast was established based on the expression of all four HER isoforms, as well as HB-EGF and related growth factors. HB-EGF did not alter proliferation, but initiated extravillous differentiation, with decreased alpha6 integrin expression, increased alpha1, and elevated cell migration. Function-blocking antibodies against EGF family members reduced basal cell motility and antibody inhibition of either HER1 or HER4 ligation prevented HB-EGF-induced integrin switching. We conclude that HER-mediated autocrine and paracrine signaling by HB-EGF or other EGF family members induces cytotrophoblast differentiation to an invasive phenotype.     

Tadalafil alleviates preeclampsia and fetal growth restriction in RUPP model of preeclampsia in mice

Background– Tadalafil, a long-acting phosphodiesterase 5 (PDE5) inhibitor, alleviates preeclampsia (PE), and decreases the fetal and infant deaths associated with fetal growth restriction (FGR) in phase II clinical trial. Recently, we demonstrated that tadalafil alleviates FGR and hypertension in the dams with PE induced by l-NAME.Objective–The aim of present study was to clarify the effect of tadalafil in another mouse model of PE, murine reduced uterine perfusion pressure (RUPP) model we have recently developed.Methods–At 14.5 dpc we performed RUPP operation in mice to induce PE, administered the animals with tadalafil or vehicle in the drinking water daily from 15.5 dpc, and sacrificed them at 18.5 dpc for analyses.Results–Tadalafil improved maternal hypertension and glomerular endotheliosis in RUPP mice. Moreover, tadalafil prolonged pregnancy period, and improved survival and growth of the embryos. RUPP increased content of sFlt-1 protein in the placenta, and tadalafil corrected it back to control levels.Conclusion– Tadalafil alleviates PE-like phenotype and FGR in RUPP murine model. RUPP model could help understand the mechanism of how tadalafil works on PE and FGR.     

Yearly hypertension screening in women with a history of pre-eclampsia: a cost-effectiveness analysis

Background

Women with a history of preeclampsia are at increased risk for future hypertension and cardiovascular disease (CVD); until now it is not clear whether preventive measures are needed.

Methods

A decision-analytic Markov model was constructed to evaluate healthcare costs and effects of screening and treatment (100 % compliance) for hypertension post preeclampsia based on the available literature. Cardiovascular events and CVD mortality were defined as health states. Outcomes were measured in absolute costs, events, life-years and quality-adjusted life-years (QALYs). Sensitivity and threshold analyses were performed to address uncertainty.

Results

Over a 20-year time horizon, events occurred in 7.2 % of the population after screening, and in 8.5 % of the population without screening. QALYs increased from 16.37 (no screening strategy) to 16.40 (screening strategy), an increment of 0.03 (95 % CI 0.01;0.05) QALYs. Total expected costs were € 8016 in the screening strategy, and € 9087 in the none screening strategy (expected saving of € 1071 (95 % CI − 3146;-87) per person).

Conclusion

Annual hypertension screening and treatment in women with a history of preeclampsia may save costs, for at least a similar quality of life and survival due to prevented CVD compared with standard care.

Electronic supplementary material

The online version of this article (doi:10.1007/s12471-015-0760-z) contains supplementary material, which is available to authorized users.