Women with endometriosis have increased levels of placental growth factor in the peritoneal fluid compared with women with cystadenomas

BACKGROUND: To assess the release of placental growth factor (PlGF) into peritoneal fluid in women with and without endometriosis, we measured its concentration with reference to disease stage, the presence of red endometriotic lesions and the phase of menstrual cycle. METHODS: Surgery was scheduled in the proliferative or secretory phase of the menstrual cycle for 59 women with (n = 35) or without (n = 24) endometriosis. The latter group comprised women undergoing surgery for ovarian cystadenomas. PlGF concentrations in the peritoneal fluid were measured using an enzyme-linked immunosorbent assay. RESULTS: PlGF concentration in the peritoneal fluid was markedly elevated in the endometriosis patients (median 189 pg/ml, interquartile range 84-475 pg/ml) as compared with the controls (88 pg/ml, 41-213 pg/ml; P < 0.001), especially in women with red lesions. Significantly greater values during the secretory phase of the menstrual cycle as compared with the proliferative phase were observed in both the control (cystadenoma) group (P < 0.05) and the endometriosis group (P < 0.001). CONCLUSIONS: Our findings suggest that production of PlGF is sensitive to the cyclic changes in ovarian steroids and may contribute to the pathogenesis of endometriosis, especially that of red lesions, by promoting neovascularization.     

人滋养细胞TLR3信号通路活化抑制血管生成因子表达

目的 研究人类妊娠早期滋养细胞Toll样受体3(TLR3)活化对胎盘血管生成相关因子表达的影响,探讨该通路在妊娠期高血压疾病中的作用.方法 以TLR3配体刺激原代滋养细胞和永生化滋养细胞系swan71,不同时间点收集上清液及细胞.ELISA测定培养上清液中sFlt-1和PIGF浓度,real-time PCR法测定上述分子mRNA表达水平.结果 Poly(I∶C)刺激swan71后24、48和120 h,sFlt-1浓度显著高于未处理组(P＜0.05).Poly(I∶C)刺激原代滋养细胞后sFlt-1 mRNA水平升高,PlGF mRNA水平下降(P＜0.05).Poly(I∶C)诱导sFlt-1 mRNA的表达呈时间和剂量依赖性,24 h时效分析见其在处理2h达到峰值,PlGF mRNA则跌至最低水平(P＜0.05).Poly(I∶C)处理8～12 h,TLR3 mRNA水平亦显著升高(P＜0.05).结论 滋养细胞TLR3信号通路激活诱导sFlt-1表达,抑制PlGF表达,导致血管生成障碍,可能参与妊娠期高血压疾病的发生.     

妊娠高血压及先兆子痫孕妇胎盘发育不全的相关因素分析*

【摘要】 目的 探讨妊娠高血压（GH）及先兆子痫（PE）孕妇胎盘发育不全的相关因素分析。 方法 选择2017年2月～2019年2月本院收治的23例妊娠期高血压孕妇（GH组）、23例先兆子痫孕妇（PE组）及26例同期就诊的正常孕妇（对照组）为研究对象。采用自由基分析系统4分析活性氧代谢物（d-ROM）和血清生物抗氧化剂（BAP）的血清衍生物。ELISA试剂盒测定可溶性Fms样酪氨酸激酶-1（sFlt-1）和胎盘生长因子（PlGF）的血清浓度。多普勒超声测量肱动脉血流介导的血管舒张（FMD）和颈动脉的内膜中层厚度（IMT）。免疫组织化学分析8-羟基-2′-脱氧鸟苷（8-OHdG）、氧化还原因子-1（ref-1）、缺氧诱导因子-1α（HIF-1α）。 结果 GH组和PE组妊娠期间收缩压和舒张压均显著升高,GH组和PE组分娩后1年收缩压显著升高,且GH组较PE组更高;GH组分娩后1年舒张压显著升高（P＜0.05）。GH组和PE组母体血清d ROM、BAP浓度显著升高,且GH组BAP浓度较PE组更高（P＜0.05）;与GH组和对照组比较,PE组的母体血清sFlt-1浓度及sFlt-1/P1GF比例显著升高（P＜0.05）;GH组和PE组母体血清PlGF浓度显著降低,且PE组较GH组更低（P＜0.05）。GH组和PE组中HIF-1α、8-OHdG阳性细胞核的比例显著升高,且PE组与GH组相比更高;与PE组和对照组比较,GH组中ref 1阳性细胞核的比例显著升高（P＜0.05）。GH组和PE组的FMD显著降低,IMT显著升高,且GH组IMT显著高于PE组（P＜0.05）。 结论 PE患者胎盘缺氧变化和DNA氧化损伤严重,并伴有抗血管生成因子的增加,且GH患者的母体器质性血管紊乱比PE患者更为严重。     

Correlation between uterine artery Doppler and the sFlt-1/PlGF ratio in different phenotypes of placental dysfunction

Objective: To explore correlations between the sFlt-1/PlGF ratio and uterine arteries (UtA) Doppler indexes in placental dysfunction-related disorders (PDD).

Methods: We prospectively included women with a singleton pregnancy with preeclampsia (PE) only (n = 22), preeclampsia with fetal growth restriction (FGR) (n = 32), FGR only (n = 12), or normal pregnancy (n = 29).

Results: In PDDs, significantly positive correlations between the sFlt-1/PlGF ratio and the mean UtA pulsatility (mPI-UtA), as well as the resistance index (mRI-UtA) were found (p = 0.015, p = 0.019, respectively), but not in normal pregnancies. PDD with signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio and mPI-UtA, was found in 50.0%, and, by the increased sFlt-1/PlGF ratio and mRI-UtA, in 65.2%. PDD without signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio but normal mPI-UtA, was found in 24.2%, and, by the increased sFlt-1/PlGF ratio but normal mRI-UtA, in 7.6%. A substantial proportion of women with signs of impaired placentation were diagnosed with FGR with or without PE.

Conclusion: In PDD, the sFlt-1/PlGF ratio and UtA Doppler indexes increase proportionally. Correlations between the sFlt-1/PlGF ratio and UtA Doppler indexes might help to distinguish between PDDs with and without impaired placentation. However, further studies are needed to explore the correlations in different phenotypes of PDD.     

Baseline placental growth factor levels for the prediction of benefit from early aspirin prophylaxis for preeclampsia prevention

ObjectivePlacental growth factor (PlGF) levels early in pregnancy are lower in women who ultimately develop preeclampsia. Early initiation of low-dose aspirin reduces preeclampsia risk in some high risk women. We hypothesized that low PlGF levels may identify women at increased risk for preeclampsia who would benefit from aspirin.Study designSecondary analysis of the MFMU High-Risk Aspirin study including singleton pregnancies randomized to aspirin 60 mg/d (n = 102) or placebo (n = 72), with PlGF collected at 13 w 0 d–16 w 6 d. Within the placebo group, we estimated the probability of preeclampsia by PlGF level using logistic regression analysis, then determined a potential PlGF threshold for preeclampsia prediction using ROC analysis. We performed logistic regression modeling for potential confounders.ResultsROC analysis indicated 87.71 pg/ml as the threshold between high and low PlGF for preeclampsia-prediction. Within the placebo group high PlGF weakly predicted preeclampsia (AUC 0.653, sensitivity/specificity 63%/66%). We noted a 2.6-fold reduction in preeclampsia with aspirin in the high-PlGF group (12.15% aspirin vs 32.14% placebo, p = 0.057), but no significant differences in preeclampsia in the low PlGF group (21.74% vs 15.91%, p = 0.445).ConclusionsUnlike other studies, we found that high rather than low PlGF levels were associated with an increased preeclampsia risk. Low PlGF neither identified women at increased risk of preeclampsia nor women who benefitted from aspirin. Further research is needed to determine whether aspirin is beneficial in women with high PlGF, and whether the paradigm linking low PlGF and preeclampsia needs to be reevaluated.CondensationHigh-risk women with low baseline PlGF, a risk factor for preeclampsia, did not benefit from early initiation of low-dose aspirin.     

Modulation of cerebral endothelial cell function by TGF-β in glioblastoma: VEGF-dependent angiogenesis versus endothelial mesenchymal transition

Glioblastoma are among the most angiogenic tumors. The molecular mechanisms that control blood vessel formation by endothelial cells (EC) in glioblastoma remain incompletely understood. Transforming growth factor-β (TGF-β) is a key regulatory cytokine that has proinvasive and stemness-maintaining autocrine properties in glioblastoma and confers immunosuppression to the tumor microenvironment. Here we characterize potential pro- and anti-angiogenic activities of TGF-β in the context of glioblastoma in vitro, using human brain-derived microvascular endothelial cells (hCMEC/D3) and glioblastoma-derived endothelial cells (GMEC) as model systems. We find that TGF-β induces vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) mRNA expression and protein release in a TGF-β receptor (TβR) II / activin-like kinase (ALK)-5-dependent manner under normoxia and hypoxia, defining potential indirect proangiogenic activity of TGF-β in glioblastoma. In parallel, exogenous TGF-β has also inhibitory effects on EC properties and induces endothelial-mesenchymal transition (EndMT) in hCMEC and GMEC. Accordingly, direct inhibition of endogenous TGF-β/ALK-5 signalling increases EC properties such as tube formation, von-Willebrand factor (vWF) and claudin (CLDN) 5 expression. Yet, the supernatant of TGF-β-stimulated hCMEC and GMEC strongly promotes EC-related gene expression and tube formation in a cediranib-sensitive manner. These observations shed light on the complex pro- and anti-angiogenic pathways involving the cross-talk between TGF-β and VEGF/PLGF signalling in glioblastoma which may involve parallel stimulation of angiogenesis and EndMT in distinct target cell populations.     

Prenatal diagnosis of mosaic trisomy 16 by amniocentesis in a pregnancy associated with abnormal first-trimester screening result (low PAPP-A and low PlGF), intrauterine growth restriction and a favorable outcome

ObjectiveWe present prenatal diagnosis of mosaic trisomy 16 by amniocentesis in a pregnancy associated with an abnormal first-trimester screening result, intrauterine growth restriction (IUGR) and a favorable outcome.Case reportA 27-year-old woman underwent amniocentesis at 18 weeks of gestation because of an abnormal first-trimester screening result with maternal serum free β-hCG of 1.474 multiples of the median (MoM), pregnancy associated plasma protein-A (PAPP-A) of 0.122 MoM and placental growth factor (PlGF) of 0.101 MoM, and a Down syndrome risk of 1/45. Amniocentesis revealed a karyotype of 47,XY,+16 [9]/46,XY [16] and an abnormal array comparative genomic hybridization (aCGH) result of arr (16) × 3 [0.54] compatible with 54% mosaicism for trisomy 16 in uncultured amniocytes. At 24 weeks of gestation, repeat amniocentesis revealed a karyotype of 47,XY,+16 [4]/46,XY [16] and an aCGH result of arr 16p13.3q24.3 (96,766–90,567,357) × 2.25 with a log₂ ratio = 0.2 compatible with 20–30% mosaicism for trisomy 16 in uncultured amniocytes. Quantitative fluorescent polymerase chain reaction (QF-PCR) excluded uniparental disomy (UPD) 16. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed 19.4% (12/62 cells) mosaic trisomy 16. Prenatal ultrasound revealed IUGR. At 36 weeks of gestation, a phenotypically normal baby was delivered with a body weight of 1900 g. The cord blood had a karyotype of 46,XY. QF-PCR analysis confirmed biparentally inherited disomy 16 in the cord blood and maternal-origin of trisomy 16 in the placenta. When follow-up at age two months, FISH analysis on 101 buccal mucosal cells and 32 urinary cells revealed no signal of trisomy 16.ConclusionMosaic trisomy 16 at amniocentesis can be associated with IUGR and an abnormal first-trimester screening result with low PAPP-A and low PlGF. Mosaic trisomy 16 without UPD 16 at amniocentesis can have a favorable outcome, and the abnormal triosmy 16 cell line may disappear after birth.