sFlt-1和PLGF与子痫前期预测

子痫前期(PE)是妊娠期特有疾病,是造成围产期不良母婴结局的主要原因。目前PE的发病机制尚不明确,尽早发现并进行干预能有效降低不良妊娠结局。可溶性血管内皮生长因子受体-1(s Flt-1)、胎盘生长因子(PLGF)均由胎盘滋养细胞分泌,分别属于抗血管内皮生长因子及血管内皮生长因子(VEGF),对于胎盘血管的健康形成至关重要。研究发现,两者能预测PE发生。本文通过复习相关文献,总结s Flt-1、PLGF与PE的相关研究,为PE的预测及治疗提供新思路。     

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.     

子痫前期预测与诊断中血管生成因子的应用价值

血管内皮生长因子、胎盘生长因子及内源性可溶性血管内皮生长因子受体不仅在子痫前期发病时表达异常，并且在临床症状出现前数周，患者血清中即可检测到其表达异常。子痫前期主要临床表现高血压、蛋白尿与血清中过多可溶性血管内皮生长因子受体有关。联合测定血管内皮生长因子、胎盘生长因子、可溶性血管内皮生长因子受体有望成为预测和早期诊断子痫前期的有效方法并应用于临床。     

子痫前期孕妇血清及尿液中VEGF、PLGF、sFlt-1水平变化及意义

目的:研究子痫前期孕妇血清及尿液中血管内皮生长因子(VEGF)、胎盘生长因子(PLGF)、可溶性血管内皮生长因子受体1(sFlt-1)水平变化与病情程度的关系,以及对子痫前期的预测价值.方法:将妊娠28～40周的19例轻度子痫前期,13例重度子痈前期孕妇作为研究组,9例正常妊娠孕妇作为对照组.采用酶联免疫吸附法检测各组孕妇血清及尿液中VEGF、PLGF、sFlt-1水平.结果:轻度子痫前期组血清及尿液VEGF、PLGF、sFlt-1水平与重度子痫前期组比较,差异均有高度统计学意义(P＜0.01).轻度子痫前期组血清及尿液ⅦGF、PLGF、sFlt-1水平与对照组比较,差异均有高度统计学意义(P＜0.01).子痫前期组,血清PLGF及sFlt-1水平高于尿液中水平.而血清VEGF水平则低于尿液中的水平.在对照组,血清的VEGF、PLGF及sFlt-1水平均高于尿中的水平.结论:孕妇血清和尿液中ⅦGF、PLGF、sFlt-1水平与子痫前期病情程度呈相关性.检测孕妇尿液中的VEGF、PLGF及sFlt-1水平可能预测子痫前期的发生.     

子痫前期预测与诊断中血管生成因子的应用价值

血管内皮生长因子、胎盘生长因子及内源性可溶性血管内皮生长因子受体不仅在子痫前期发病时表达异常,并且在临床症状出现前数周,患者血清中即可检测到其表达异常.子痫前期主要临床表现高血压、蛋白尿与血清中过多可溶性血管内皮生长因子受体有关.联合测定血管内皮生长因子、胎盘生长因子、可溶性血管内皮生长因子受体有望成为预测和早期诊断子痫前期的有效方法并应用于临床.     

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。     

α7 nAChR和sFlt-1mRNA在重度子痫前期患者胎盘的表达

目的:检测α7烟碱乙酰胆碱受体(alpha 7 nicotini cacetylcholine receptor,α7nAChR)和可溶性血管内皮生长因子受体-1(soluble fms-like tyrosine kinase-1,sFlt-1)在重度子痫前期患者胎盘组织中mRNA的表达水平,探讨它们在子痫前期发生发展中的作用。方法:用半定量逆转录聚合酶链反应(RT-PCR)技术检测18例重度子痫前期患者和12例正常妊娠孕妇的胎盘。结果:(1)α7nAChR和sFlt-1mRNA在正常孕妇和重度子痫前期患者胎盘组织中均有表达。(2)重度子痫前期患者α7nAChR和sFlt-1mRNA的表达水平上调,且两者上升水平呈正相关。结论:胎盘组织中α7nAChR和sFlt-1mRNA的过度表达可能与子痫前期发病有关,参与了子痫前期的病理生理过程。     

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。     

子痫前期发病机制初探

目的探讨子痫前期患者生化指标及分子机制。方法收集2011年3月至2015年12月48例子痫前期轻度患者,32例子痫前期重度患者,以及50例正常妊娠妇女血清及胎盘,检测血清中胎盘生长因子(placenta growth factor,PLGF),可溶性血管内皮生长因子受体1(soluble fms-like tyrosine kinase-1,s Flt-1)的水平,以及分析胎盘中活性氧(reactive oxygen species,ROS)与抗氧化基因的表达情况。结果在孕12~16周、孕26~30周及孕37~41周,轻度与重度组PLGF水平均显著低于正常妊娠组水平(P0.05);在孕26~30周及孕37~41周,轻度与重度组s Flt-1水平显著高于正常妊娠组水平(P0.05);轻度与重度组胎盘氧化应激明显增强,表现为ROS水平增加及抗氧化应激基因的上调。结论孕妇血清中PLGF和s Flt-1水平变化与子痫前期相关;ROS异常增加是子痫前期发生的分子基础。     

Mid-pregnancy levels of angiogenic markers as indicators of pathways to preterm delivery

Objective: To determine whether mid-pregnancy levels of angiogenic markers were associated with increased risk of preterm delivery (PTD). Methods: We studied a subcohort from the Pregnancy Outcomes and Community Health Study for whom mid-pregnancy angiogenic markers (soluble fms-like tyrosine kinase-1 [sFlt-1], soluble endoglin [sEng] and placental growth factor [PlGF]) and covariate data were available (N = 1301). Angiogenic marker levels were grouped as high/not high (sFlt-1 and sEng), low/not low (PlGF) and high/intermediate/low (sFlt-1). Associations between levels of angiogenic markers and PTD/PTD subtype were determined for women who were nonsmokers during pregnancy (N = 933). Results: Low PlGF and high sEng were associated with medically-indicated PTD and PTD <35 weeks, largely due to preeclampsia (PE). Excluding PE and small-for-gestational-age infants, low sFlt-1 was positively associated with medically-indicated PTD. Conclusions: Among nonsmokers, mid-pregnancy levels of angiogenic markers may mark multiple pathways leading to PTD, only one attributable to PE.     

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.     

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.     

Angiogenesis-related biomarkers (sFlt-1/PlGF) in placental mesenchymal dysplasia

Determination of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) in the maternal serum is expected to aid in the monitoring and decision-making process of women at risk for placental dysfunction. We report two cases of placental mesenchymal dysplasia (PMD) with sFlt-1/PlGF correlation. The first case is a dichorionic twin pregnancy with one fetus affected by PMD and Beckwith–Wiedemann syndrome in which a high value of sFlt-1/PlGF was found, coinciding with acute maternal and fetal wellbeing decline at 31 weeks. The second case corresponds to a singleton pregnancy diagnosed of PMD with normal sFlt-1/PlGF and favorable outcome.     

可溶性血管内皮生长因子受体-1在子痫前期胎盘及在外周血的研究

目的研究可溶性血管内皮生长因子受体-1(sFlt-1) mRNA在正常妊娠和子痫前期胎盘中的表达差异及相应的母体外周血中sFlt-1水平的变化。方法选取15例子痫前期孕妇(子痫前期组)和14例孕周与之相匹配的血压正常妊娠孕妇(对照组),用ELISA方法测定其外周血中sFlt-1的水平;并应用实时荧光定量PCR测定两组胎盘组织中sFlt-1 mRNA水平。结果外周血中sFlt-1的水平子痫前期组明显高于对照组,分别为(16.9±8.32)μg/L、(5.48±2.09)μg/L,两者差异有显著性(P<0.05)。sFlt-1 mRNA在两组胎盘中均有表达,在子痫前期组的表达明显高于对照组的表达分别为(4.11±4.09)、(1.69±1.61),两者差异有显著性(P<0.05)。子痫前期组血清sFlt-1水平与24h尿蛋白定量呈明显正相关(r=0.741,P<0.05)。结论sFlt-1 mRNA在子痫前期组孕妇的外周血中及胎盘组织表达升高,可能与子痫前期的病因及病理生理有关。