血清可溶性血管内皮生长因子受体与子痫前期发病的关系

目的探讨血清中可溶性血管内皮生长因子受体1(sFlt-1)的变化及其与子痫前期发病的关系。方法(1)应用半定量RT-PCR技术检测10例重度子痫前期患者(子痫前期组)及10例足月正常妊娠妇女(正常妊娠组)的胎盘组织中sFlt-1mRNA表达水平。(2)应用酶联免疫吸附试验(ELISA)法测定35例重度子痫前期患者(子痫前期1组)及35例正常足月妊娠妇女(正常妊娠1组)外周血中sFlt-1水平。(3)ELISA测定20例重度子痫前期患者(子痫前期2组)及20例正常足月妊娠妇女(正常妊娠2组)胎盘附着处子宫静脉血中sFlt-1水平。(4)ELISA测定10例早孕(早孕组)及10例中孕(中孕组)妇女外周血中sFlt-1水平。结果(1)子痫前期组胎盘组织中sFlt-1mRNA表达水平为0.95±0.04,明显高于正常妊娠组的0.64±0.15,两组比较,差异有统计学意义(P<0.01)。(2)子痫前期1组孕妇外周血清中sFlt-1水平为(5640±3191)ng/L,明显高于正常妊娠1组的(2194±635)ng/L,两组比较,差异有统计学意义(P<0.01)。(3)子痫前期2组孕妇子宫静脉血清中sFlt-1水平为(7673±2296)ng/L,明显高于正常妊娠2组的(3057±785)ng/L,两组比较,差异有统计学意义(P<0.01)。(4)早、中孕组孕妇外周血清中sFlt-1水平分别为(32±20)ng/L及(994±302)ng/L。结论(1)子痫前期患者外周血中sFlt-1水平明显增高;(2)血清中sFlt-1水平随孕周增加而升高,并可能与子痫前期的发病有关。     

可溶性血管内皮生长因子受体1与子痫前期研究进展

可溶性血管内皮生长因子受体1（sFh1）是血管内皮生长因子受体1的剪接变体．sFit-1能阻断血管内皮生长因子和胎盘生长因子的生物学效应，因而造成全身内皮功能失调，产生高血压、蛋白尿等临床表现。子痫前期发病前5周循环中sFh1水平就有显著升高，子痫前期患者体内高水平的sFh1可作为预测指标。拮抗sFh1药物在子痫前期及子痫治疗中的价值值得进一步探讨。     

可溶性血管内皮生长因子受体1与子痫前期研究进展

可溶性血管内皮生长因子受体1(sFlt1)是血管内皮生长因子受体1的剪接变体,sFlt-1能阻断血管内皮生长因子和胎盘生长因子的生物学效应,因而造成全身内皮功能失调,产生高血压、蛋白尿等临床表现.子痫前期发病前5周循环中sFlt1水平就有显著升高,子痫前期患者体内高水平的sFlt1可作为预测指标.拮抗sFlt1药物在子痫前期及子痫治疗中的价值值得进一步探讨.     

可溶性血管内皮生长因子受体1对子痫前期的早期预测价值

目的探讨血清可溶性血管内皮生长因子受体1(sFlt-1)水平变化对子痫前期的早期预测价值。方法采用酶联免疫吸附法检测172例妊娠26～28周孕妇的血清sFlt-1及血管内皮生长因子(VEGF)水平,并随访至分娩,其中16例发展为子痫前期(子痫前期组),另外156例正常妊娠者为对照组。结果子痫前期组患者血清sFlt-1、VEGF分别为(11．4±6．2)μg/L、(26±4)ng/L,对照组分别为(4．5±2．1)μg/L、(29±4)ng/L,两组sFlt-1水平比较,差异有统计学意义(P＜0．01);两组VEGF水平比较,差异无统计学意义(P＞0．05)。伴胎儿生长受限的子痫前期患者(8例)及妊娠32周前发病的子痫前期患者(6例)血清sFlt-1水平分别为(14．0±6．8)、(14．4±6．7)μg/L,均分别明显高于未伴胎儿生长受限及妊娠32周后发病的子痫前期患者的(9．0±4．1)、(8．9±4．0)μg/L,差异有统计学意义(P＜0．05)。以sFlt-1水平8．75μg/L为界限值,预测子痫前期的敏感度为87．5%,特异度为97．4%,阳性预测值为80．0%,阴性预测值为88．5%。结论血清sFlt-1水平可作为子痫前期发病的早期预测指标。     

可溶性血管内皮生长因子受体-1与胎盘生长因子在子痫前期

归纳子痫前期的病理生理过程以及可溶性血管内皮生长因子受体-l（sFlt-1）、胎盘生长因子（PLGF）与子痫前期的研究情况,PLGF是血管内皮生长因子（VEGF）家族成员之一,PLGF与Flt-1受体结合时,发挥促血管生成和促绒毛滋养细胞增殖、浸润的效应,而这些生物学功能均可被sFlt-1阻断,且sFlt-1对PLGF具有强效的拮抗作用,调节PLGF的功能。在子痫前期妊娠妇女血清中sFlt-1的水平升高,早于疾病的发生。子痫前期患者血浆中PLGF的水平降低。总结sFlt-1、PLGF预测诊断子痫前期发生及病情严重程度的研究进展,探讨sFlt-1、PLGF在子痫前期临床诊断中的意义。     

可溶性血管内皮生长因子受体1在子痫前期患者胎盘组织中的表达及意义

目的探讨可溶性血管内皮生长因子受体1(sFlt-1)在子痫前期患者胎盘组织中的mRNA及蛋白表达水平变化及其意义。方法(1)采用免疫组化方法及RT-PCR技术分别检测30例子痫前期患者(子痫前期组,其中轻度子痫前期11例,重度子痫前期19例)及45例健康孕妇(对照组,其中早期妊娠18例、中期妊娠12例、晚期妊娠15例)胎盘组织中sFlt-1的蛋白及mRNA表达水平。(2)采用酶联免疫吸附试验(ELISA)测定各组孕妇血清中血管内皮生长因子(VEGF)及sFlt-1水平。结果(1)子痫前期组胎盘组织中sFlt-1 mRNA表达水平为0．90±0．11,对照组晚期妊娠妇女为0．80±0．06,两者比较,差异有统计学意义(P<0．01)。子痫前期组重度患者为0．93±0．12,子痫前期组轻度患者为0．85±0．05,两者比较,差异也有统计学意义(P<0．05)。(2)sFlt-1蛋白在子痫前期组患者胎盘组织中的表达水平为0．156±0．008,对照组中晚期妊娠妇女为0．143±0．009,两者比较,差异有统计学意义(P<0．01);子痫前期组重度患者sFlt-1蛋白表达水平为0．159±0．008,子痫前期组轻度患者为0．151±0．005,两者比较,差异也有统计学意义(P<0．05)。(3)子痫前期组孕妇血清VEGF、sFlt-1水平分别为(19．3±2．9)ng／L、(30．2±13．7)μg／L,对照组晚期妊娠妇女为(30．2±3．1)ng／L、(7．4±3．1)μg／L,两者比较,差异有统计学意义(P<0．01)。(4)对照组孕妇血清sFlt-1水平与胎盘sFlt-1蛋白及mRNA表达水平呈正相关关系(r=0．439,P<0．01;r=0．314,P< 0．05);子痫前期组孕妇血清sFlt-1水平与胎盘sFlt-1蛋白及mRNA表达水平也呈正相关关系(r= 0．383,r=0．372;P均<0．05)。结论子痫前期患者胎盘组织中sFlt-1 mRNA表达水平上调及sFlt-1蛋白过度表达,可引起循环中sFlt-1水平升高,从而参与子痫前期的病理生理过程。     

血管内皮生长因子受体2在子痫前期患者胎盘中的表达及其意义

目的探讨子痫前期患者胎盘中血管内皮生长因子受体2（KDR）的表达与胎盘血管病变的关系,研究子痫前期的发病机制。方法对中国医科大学附属第二医院2004年1至11月间收治的重度子痫前期患者22例、轻度子痫前期患者20例和同期正常妊娠妇女20例,采用免疫组化SP法检测其胎盘中KDR的表达情况,记数胎盘间质的平均微血管密度（MVD）值。结果子痫前期重度患者胎盘中KDR的表达显著低于轻度患者和正常孕妇（P〈0.01）,子痫前期轻度组较正常对照组KDR表达明显降低（P〈0.05）。子痫前期重度组患者胎盘中MVD值明显低于轻度组和正常对照组（P〈0.01）,子痫前期轻度组较正常对照组MVD值降低（P〈0.05）。子痫前期患者和正常孕妇胎盘中KDR表达与MVD值的变化呈显著正相关（r=0.855,P〈0.01）。结论KDR表达水平降低可能参与引起胎盘血管发育不良,从而导致子痫前期的发生和发展。     

可溶性血管内皮生长因子受体1与子痫前期的关系研究进展

子痫前期是妊娠期特有疾病,以高血压和蛋白尿等为临床特征,影响母亲和新生儿的患病率和死亡率。尽管病因至今不明,但多数学者认为其发病与胎盘因子进入母体的血循环引起血管内皮的损伤有关。近年来发现,抗血管生成因子如内皮因子、可溶性血管内皮生长因子受体1(sFlt-1)以及胎盘生长因子都与子痫前期的发生有关。对sFlt-1分子结构及作用、调节因素、相关信号转导途径及其在子痫前期发病机制中的研究结果作一综述。     

可溶性血管内皮生长因子受体-1(sFlt-1)与不明原因复发性流产的相关性研究

目的:探讨可溶性血管内皮生长因子受体(sFlt-1)与原因不明复发性流产(URSA)的相关性。方法:①采用酶联免疫吸附试验法(ELISA)测定30例原因不明复发性流产胚胎停育患者(URSA组)和30例正常早孕孕妇(对照组)血清sFlt-1水平;②采用逆转录聚合酶链反应(RT-PCR)方法测定各组孕妇绒毛组织sFlt-1mRNA表达水平。结果:复发性流产胚胎停育组与正常早孕对照组血清sFlt-1水平分别为13796.67±11917.08ng/L和3540.67±2989.80ng/L;复发性流产胚胎停育组与正常早孕对照组绒毛组织sFlt-1mRNA表达水平两组计量资料不符合正态分布,用Mann-Whitney秩和检验比较,RSA组sFlt-1mRNA均秩为41.37,正常组sFlt-1mRNA均秩为19.63,P<0.01,组间差异非常显著性意义(P<0.01)。结论:sFlt-1表达异常与复发性流产具有相关性,其表达水平升高可能参与RSA发生的病理生理过程。     

跨膜型血管内皮生长因子受体1在子痫前期患者胎盘组织中的表达及其意义

目的研究跨膜型血管内皮生长因子受体1(Flt-1)在子痫前期患者胎盘组织中的表达变化及其意义。方法采用RT-PCR方法检测20例子痫前期患者(观察组)胎盘组织中Flt-1mRNA的相对表达量[以Flt-1与β肌动蛋白(β-actin)电泳条带吸光度(A)值的比值表示],并以20例正常孕妇(对照组)为对照;采用蛋白印迹(westernblot)法检测和比较两组各18例胎盘组织中Flt-1的蛋白相对表达量[其余4例标本因蛋白提取不理想而废弃,以Flt-1与磷酸甘油醛脱氢酶(GAPDH)电泳条带A值的比值表示]。结果两组孕妇胎盘组织中均有Flt-1的表达,观察组孕妇胎盘组织Flt-1mRNA相对表达量为2·25±0·19,对照组为1·23±0·29,两组比较,差异有统计学意义(P<0·05);观察组孕妇胎盘组织Flt-1蛋白相对表达量为2·67±1·19,对照组为0·94±0·51,两组比较,差异也有统计学意义(P<0·05)。结论Flt-1可能参与了子痫前期的病理生理过程。     

A comparison of the diagnostic utility of the sFlt-1/PlGF ratio versus PlGF alone for the detection of preeclampsia/HELLP syndrome

Objective: The Elecsys^® immunoassay sFlt-1/PlGF ratio and the Triage^® PlGF assay were compared (in a prospective, multicenter, case-control study) for diagnosis of preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Methods: Women in European perinatal care centers with singleton pregnancies were enrolled: 178 cases had confirmed preeclampsia and 391 controls had normal outcome. Patients in the preeclampsia/HELLP syndrome group were matched pairwise by gestational week to healthy controls (1:2). Maternal blood samples were analyzed using (a) fully automated Elecsys PlGF and Elecsys sFlt-1 immunoassays with two cutoffs (early-onset [<34 weeks] ≤33, ≥85; late-onset [≥34 weeks] ≤33, ≥110), and (b) Triage PlGF immunoassay (single cutoff). Diagnostic performance and utility were assessed. Results: Respectively, 83 and 95 women had early-onset or late-onset preeclampsia/HELLP syndrome. The overall diagnostic performance of the Elecsys immunoassay sFlt-1/PlGF ratio (area under the curve [AUC] 0.941) was higher than for Triage PlGF (AUC 0.917). The Elecsys immunoassay sFlt-1/PlGF ratio sensitivity and specificity was: 94.0% (95% confidence interval [CI] 86.5–98.0) and 99.4% (95% CI: 96.8–99.9) for early-onset preeclampsia; and 89.5% (95% CI: 81.5–94.8) and 95.4% (95% CI: 91.7–97.8) for late-onset preeclampsia. The Triage assay sensitivity and specificity was: 96.4% (95% CI: 89.8–99.3) and 88.5% (95% CI: 82.8–92.8) (early-onset); and 90.5% (95% CI: 83–96) and 64.5% (95% CI: 57.8–70.9) (late onset). Conclusions: The fully automated Elecsys immunoassay sFlt-1/PlGF ratio provides improved diagnostic utility over the Triage PlGF assay with improved specificity for the clinical management of pregnant women with suspected preeclampsia/HELLP syndrome.     

胎盘微环境改变与子痫前期

胎盘对于胎儿发育至关重要,胎儿血与母体血在胎盘单位内进行养分交换。子痫前期发病的关键环节即为滋养细胞浸润不足引起的对子宫螺旋动脉重塑障碍。可溶性血管内皮生长因子受体-1与胎盘生长因子的比值在子痫前期的发病、诊断及不良妊娠结局的发生率中可能有重要预测价值。     

Serum heme oxygenase 1 (HO-1), soluble FMS like tyrosine kinase (sFlt-1) level,and neonatal outcome in early onset,late onset preeclampsia,and normal pregnancy

ABSTRACT

Objective: To compare the level of serum heme oxygenase 1 (HO-1), soluble FMS like tyrosine kinase (sFlt-1), and neonatal outcome in early onset preeclampsia (EO-PE), late onset preeclampsia (LO-PE), and normal pregnancy (NP).

Methods: In this prospective observational case control study, HO-1 and sFlt-1 levels were measured in blood samples within 24 h of hospital admission. Preeclampsia cases were divided into two groups based on gestational age at delivery: EO-PE (<34 weeks) and LO-PE (≥34 weeks). A total of 45 patients were involved in this study.

Result: Maternal serum level of sFlt-1 was higher in EO-PE than LO-PE and NP groups (mean ± SD; 14.50 ± 17.12 ng/ml vs 5.20 ± 6.69 ng/ml vs 2.72 ± 1.2 ng/ml [p = 0.020]. Maternal serum level of HO-1 was not different between EO-PE, LO-PE, and NP groups (p = 0.681). Birthweights were significantly lower in the EO-PE group compared with the LO-PE and NP groups (1580 ± 536 g vs 2635 ± 578 g vs 3010 ± 371 g [p = 0.000]). The rate of small for gestational age infant (26.7% vs 6.7% vs 0%; p = 0.046) and perinatal death (20% vs 0 vs 0; p = 0.037) was also significantly higher in EO-PE compared to LO-PE and NP. The maternal sFlt-1 level was negatively correlated with birthweight (p = 0.006; CC = ?0.445).

Conclusion: This study did not find a correlation between maternal HO-1 levels and sFlt-1 levels. Maternal serum sFLt-1 levels in preeclampsia were higher in EO-PE and were associated with a worse perinatal outcome.     

Angiogenic factors for prediction of preeclampsia and intrauterine growth restriction onset in high-risk women: AngioPred study

Objective: The study aimed to compare the level of two angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), for the prediction of preeclampsia and intrauterine growth restriction in high-risk pregnant women.

Methods: A prospective multicenter cohort study of 200 pregnant patients was conducted between June 2008 and October 2010. sFlt1 and sEng were measured by enzyme-linked immunosorbent assay.

Results: Forty-five patients developed a placenta-mediated adverse pregnancy outcome. Plasma levels of sFlt1 and sEng were higher in patients who will experience a preeclampsia at 28, 32, and 36 weeks compared with patients with no complication. The same results were observed for intrauterine growth restriction. Plasma levels of sFlt1 and sEng were not significantly different for patients with preeclampsia compare to patients with intrauterine growth restriction. Patients with early pre-eclampsia (PE) had very high rates of angiogenic factors at 20, 24, and 28 weeks. Patients with late PE and early and late intrauterine growth retardation (IUGR) had high rates at 32 and 36 weeks.

Conclusion: In high-risk women, angiogenic factors are disturbed before the onset of preeclampsia and this is true for intrauterine growth restriction.     

Do the physiological aging of the placenta and the changes in angiogenesis marker sFlt-1 and PlGF concentrations predispose patients to late-onset preeclampsia?

Objective: Aging of the placenta is associated with natural processes that impair its functions. The processes are related to both oxidative stress exacerbation and the occurrence of higher concentrations of disordered angiogenesis markers. Both these types of processes are known to play roles in the development of preeclampsia. We attempted to show that natural ageing of the placenta can be one of the cofactors contributing to the development of late-onset preeclampsia.

Patients, materials and methods: 159 pregnant patients were divided into four groups: Two of preeclampsia patients and two of patients with physiological pregnancies, depending on the gestational age. For each group, disordered angiogenesis markers sFlt-1 and PlGF before and after 34 weeks of gestation and in particular stages of gestation were analyzed.

Results: Lower PlGF and sFlt-1/PlGF ratio values were found in cases of late-onset preeclampsia. In physiological pregnancies, sFlt-1 values were observed to increase and PlGF values to decrease with gestational age. An association was shown to exist between disordered angiogenesis markers and gestational age both in preeclampsia and physiological pregnancies.

Conclusions: (1) Analyses of disordered angiogenesis markers in early- and late-onset preeclampsia patients and patients with physiological pregnancies allow for a suggestion that natural “ageing of the placenta” and placental hypoperfusion lesions exacerbating with the advancing gestational age are some of the causes of late-onset preeclampsia. (2) Cases of early-onset preeclampsia are associated with more severe changes of disordered angiogenesis marker concentrations, which may be indicative of a more considerable impairment of placental perfusion in such patients. (3) In the course of the physiological pregnancy, there is a gradual increase in sFlt-1 and decrease in PlGF, which implies an elevated angiogenesis disorder that progresses with the gestational age.