sFlt-1及缺氧因素导致子痫前期孕鼠模型滋养细胞凋亡的分析

目的:探讨可溶性血管内皮因子受体-1(sFlt-1)及缺氧因素对子痫前期(PE)孕鼠动物模型滋养细胞凋亡的作用。方法:将120只孕鼠随机分为对照组(A组)和PE模型组(B、C、D组)。建立以L-NAME、PS/PC、STBM全面的复合PE和体外sFlt-1浓度孕鼠模型。妊娠10天开始、B、D组孕鼠腹腔注射sFlt-1,A、C组腹腔注射0.9%生理盐水,均持续13天。妊娠第22天测定孕鼠血压及蛋白尿。断鼠尾取静脉血,ELISA法检测各组孕鼠血浆sFlt-1水平。剖宫产取各组孕鼠胎盘绒毛组织清洗后行原代滋养细胞组织皿培养。A、B、C、D组滋养细胞分别于正常氧压、50ng/ml sFlt-1 2ml+正常氧压、低氧和50ng/ml sFlt-1 2ml+低氧培养箱中培养。48h后,收集培养的原代滋养细胞。流式细胞技术检测细胞调亡;Western blot法检测凋亡相关蛋白Bax、Bcl-2及Caspase-3表达。结果:对照组与PE模型组孕鼠的血浆sFlt-1水平、收缩压、舒张压及尿蛋白指标比较,差异有统计学意义(P0.01);PE模型组的胎盘滋养细胞凋亡率与对照组(3.95%)比较,差异有统计学意义(P0.01),PE模型组间两两比较,差异有统计学意义(P0.05)。与对照组比较,PE模型组胎盘组织中的促凋亡蛋白Bax明显上调,抑凋亡蛋白Bcl-2明显下调,凋亡执行蛋白caspase-3表达上调;PE模型组两两比较,差异均有统计学意义(P0.05)。结论:sFlt-1及缺氧因素与PE滋养细胞过度凋亡发生密切相关,两者促进PE的发生发展。     

缺氧对滋养细胞sFlt-1及VEGF基因及蛋白表达的影响

目的:探讨缺氧对滋养细胞可溶性血管内皮生长因子受体1(soluble fims-like tyrosine kinase receptor-1,sFlt-1)及血管内皮生长因子(vascular epithelial growth factor,VEGF)表达的影响。方法:CoCl2诱导人早孕绒毛滋养细胞系TEV-1化学缺氧,分别于0h、24h、48h、72h、96h、120h用Real-time RT-PCR法检测滋养细胞中sFlt-1及VEGF mRNA表达,ELISA法检测细胞培养上清液中sFlt-1及VEGF蛋白表达。结果:滋养细胞缺氧72h后,胞质内可见明显空泡。滋养细胞sFlt-1mRNA及蛋白表达随缺氧时间的延长逐渐升高,且与缺氧72h、96h、120h间差异有显著性(P<0.05)。而滋养细胞VEGF mRNA及蛋白表达随缺氧时间的延长呈现出先上升后下降的趋势,并于缺氧48h升高达到峰值(P<0.05)。结论:不同的缺氧时间对滋养细胞VEGF及sFlt-1表达具有重要的调控作用。慢性缺氧可能导致滋养细胞sFlt-1及VEGF表达平衡失调,从而参与子痫前期的发生、发展。     

缺氧小鼠滋养细胞HMGB1通过TLR4增加内皮细胞通透性

目的:探讨高迁移率族蛋白1-Toll样受体4(HMGB1-TLR4)信息途径在子痫前期(PE)内皮细胞屏障功能障碍过程中的作用。方法:原代培养C57BL/6小鼠胎盘滋养细胞(PMT)与腹主动脉内皮细胞(MAECs),PMT或HMGB1 siRNA干预后的PMT缺氧培养,将缺氧培养PMT上清或rHMGB1作用于MAECs。检测缺氧培养PMT的细胞活性、细胞凋亡、高迁移率族蛋白(HMGB1)基因与蛋白表达水平;检测缺氧培养PMT上清处理MAECs后,Toll样受体4(TLR4)蛋白表达及单层细胞通透性。再利用TLR4基因敲除小鼠(TLR4-/-)MAECs,观察缺氧培养PMT上清对TLR4基因敲除MAECs通透性的改变。结果:缺氧24h可诱导PMT HMGB1 mRNA、蛋白表达增加,缺氧培养上清HMGB1含量显著高于常氧培养组(P0.05);PMT缺氧培养上清可明显增加MAECs单层细胞的通透性及TLR4蛋白表达,siRNA沉默PMT HMGB1或MAECs TLR4基因敲除可逆转PMT缺氧培养诱导的MAECs单层细胞通透性(P0.05)。结论:缺氧小鼠滋养细胞释放HMGB1通过TLR4途径增加MAECs通透性。     

子痫前期滋养细胞sFlt-1和HIF-1α表达及细胞功能在低氧条件下的变化

目的探讨低氧对子痫前期滋养细胞中可溶性血管内皮生长因子受体-1（sFlt-1）和缺氧抑制因子-1α（HIF-1α）的表达及滋养细胞凋亡和侵袭能力的影响。方法取正常妊娠及子痫前期孕妇终止妊娠后的胎盘绒毛组织,分离培养滋养细胞。分为：对照组（正常孕妇）：21%O2浓度培养;子痫前期组：分别行21%O2浓度（21%O2组）和1%O2浓度（1%O2组）培养。采用细胞免疫荧光检测滋养细胞密度,实时定量-多聚酶链反应（real tima-PCR）和蛋白印记（Western Blot）法检测滋养细胞中sFlt-1和HIF-1αmRNA及蛋白的表达,TUNNEL法检测滋养细胞调亡,Transwell测定滋养细胞的侵袭能力。结果子痫前期21%O2组、1%O2组与对照组sFlt-1mRNA的表达分别为（2.87±1.94）ng/ml、（3.51±1.25）ng/ml和（1.93±0.77）ng/ml,HIF-1αmRNA的表达分别为（2.79±0.64）ng/ml、（1.77±0.23）ng/ml和（3.63±0.38）,三组比较,差异均有统计学意义（P均〈0.01）。21%O2组、1%O2组与对照组sFlt-1蛋白分别为（4.99±1.77）μg/ml、（7.02±1.23）μg/ml和（3.83±0.63）μg/ml,HIF-1α蛋白分别为（3.83±0.63）μg/ml、（3.06±0.25）μg/ml和（7.73±1.02）μg/ml,三组比较,差异均有统计学意义（P均〈0.01）。21%O2组、1%O2组与对照组72h滋养细胞凋亡分别为（15.81±3.93）个、（20.18±3.47）个和（6.64±1.37）个,侵袭数目分别为（10.05±1.92）个、（18.65±4.17）个和（2.22±0.43）个,三组比较,差异均有统计学意义（P均〈0.01）。结论子痫前期和正常妊娠孕妇滋养细胞均对低氧敏感,低氧对滋养细胞sFlt-1和HIF-1α的表达有影响,且低氧条件下促使滋养细胞凋亡及侵袭能力强化。     

子痫前期中sFlt-1的研究进展

子痫前期(PE)为妊娠期特有的多器官受损疾病,是目前导致母儿发病及死亡的主要原因之一,且其发生率呈逐年增长趋势。尽管相关治疗方案已制定,但由于PE发病机制尚未阐明,导致治疗效果欠佳、不良妊娠结局常有发生。因此,探讨此病的发病机制具有重要意义。近年sFlt-1在PE发病中的作用备受关注。相关研究已证实,可溶性血管内皮生长因子受体-1(sFlt-1)参与此病的发生发展,并与其严重程度呈正相关。本文通过综述sFlt-1在PE中的研究进展,以对这一新的学说做一阐述。     

缺氧调控滋养细胞MMP-9/TIMP-1表达及侵袭能力的体外研究

目的:探讨缺氧对滋养细胞的生长、MMP-9/TIMP-1基因表达以及侵袭能力的影响。方法:滋养细胞在正常及二氯化钴(CoCl2)所致化学缺氧条件下的培养。MTT法检测正常及缺氧条件下滋养细胞的生长状况。细胞爬片确定MMP-9/TIMP-1在滋养细胞中的定位及缺氧前后的蛋白表达。荧光定量PCR检测滋养细胞中MMP-9和TIMP-1基因表达。Transwell侵袭模型检测滋养细胞的侵袭能力变化。结果:(1)MMP-9和TIMP-1均表达于滋养细胞的包膜和胞浆。在缺氧条件下,MMP-9和TIMP-1蛋白表达均呈上调趋势,且在缺氧48h时最明显(P0.01);(2)150、300μmol/L CoCl2均可显著抑制滋养细胞的增殖,其中300μmol/L抑制作用更明显,与150μmol/L比较,差异有统计学意义(P0.01);(3)缺氧条件下,MMP-9和TIMP-1的基因表达均增加,以48h最为显著;但MMP-9/TIMP-1比值降低,以72h最显著(P0.01);(4)缺氧后滋养细胞侵袭力显著降低(P0.05)。结论:缺氧能抑制滋养细胞增殖、促进滋养细胞分泌MMP-9和TIMP-1,但MMP-9/TIMP-1比值降低,使滋养细胞的侵袭力减弱。     

子痫前期血清对滋养-内皮细胞共培养体系滋养细胞侵袭力和内皮细胞凋亡的影响

目的:探讨子痫前期血清对滋养-内皮细胞共培养体系滋养细胞侵袭力改变及对内皮细胞凋亡的影响.方法:选择正常足月妊娠剖宫产孕妇10例(正常对照组),子痫前期患者20例(子痫前期组).采用组织块贴壁法培养人孕早期细胞滋养细胞(CTB),胰酶消化法培养正常妊娠人脐静脉内皮细胞(HUVEC),传代后建立滋养细胞与脐静脉内皮细胞共培养模型,并分别加入正常对照组和子痫前期组患者静脉血清培养24小时;Transwell小室检测细胞滋养细胞的侵袭能力;流式细胞学检测人脐静脉内皮细胞凋亡率;逆转录-聚合酶链反应(RT-PCR)检测细胞滋养细胞MMP-2、MMP-9mRNA及人脐静脉内皮细胞自杀相关因子(Fas)mRNA的表达.结果:子痫前期患者血清共培养体系的细胞滋养细胞的侵袭能力低于正常对照组(P<0.01);人脐静脉内皮细胞凋亡率明显低于正常对照组(P<0.05);MMP-2、MMP-9和FasmRNA的表达明显下降(P<0.05).结论:子痫前期血清可能通过降调细胞滋养细胞MMP-2、MMP-9表达而影响滋养-内皮细胞共培养体系滋养细胞的侵袭能力,并且其滋养-内皮细胞共培养体的内皮细胞Fas的表达异常可能与内皮细胞凋亡下降有关.提示滋养细胞MMP-2、MMP-9、Fas/Fasl的表达异常可能参与了子痫前期子宫螺旋动脉重铸障碍的病理过程.     

子痫前期患者血清可通过sFlt-1-CAV1途径增加肾小球内皮细胞通透性

目的:探讨子痫前期(PE)血清中可溶性血管内皮生长因子受体1(sFlt-1)对肾小球内皮细胞(HRGECs)通透性的影响机制。方法:收集20例PE与正常孕妇外周血清,ELISA法检测孕妇外周血中sFlt-1含量。利用PE血清及重组sFlt-1(rsFlt-1)蛋白处理HRGECs,细胞接种于transwell小室,体外细胞培养分组:正常孕妇血清处理组(NG组),PE血清处理组(PE组),正常孕妇血清+rsFlt-1处理组,PE+sFlt-1抑制剂处理组,PE血清+CAV1抑制剂处理组。Evens-blue检测HRGECs对大分子蛋白通透性改变;Western blot法检测caveolin-1(CAV1)蛋白表达。结果:PE血清sFlt-1含量明显高于正常对照组;PE血清、rsFlt-1可使HRGECs对大分子蛋白通透性及CAV1蛋白表达增加。sFlt-1抑制剂、CAV1抑制剂可抑制PE血清、rsFlt-1导致的HRGECs对大分子蛋白通透性增加。结论:PE患者血清可通过sFlt-1-CAV1信号通路增加肾小球内皮细胞对大分子蛋白的通透性,CAV1表达异常可能参与蛋白尿的产生。     

sFlt-1/PlGF预测子痫前期的临床局限性和实践探索方向

胎盘灌注不足而导致的胎儿-胎盘单位的缺血和缺氧,是子痫前期(preeclampsia,PE)发病中的重要环节之一.血管活性因子为应对缺氧产生的一系列变化可以作为预测、诊断及监测PE的重要手段.fms样酪氨酸激酶1(fms-like tyro-sine kinase 1,Flt-1)的剪接变异体可溶性Flt-1(sFlt...     

凋亡、坏死合体滋养细胞微粒对内皮细胞增殖与凋亡的影响

目的:探讨凋亡、坏死合体滋养细胞微粒对人脐静脉内皮细胞(HUVECs)增殖、凋亡的影响。方法:培养原代HUVECs,物理方法诱导滋养细胞凋亡、坏死。采用三步超速离心法制备凋亡合体滋养细胞微粒(a STBM)、坏死合体滋养细胞微粒(n STBM)(实验组),同时制备RBC膜(对照组),并检测胎盘碱性磷酸酶(PLAP)含量。将不同浓度(20、80、320μg/ml)a STBM、n STBM和RBC膜分别与HUVECs共同孵育4、16、32h。采用MTT法检测细胞增殖抑制率,采用流式细胞仪AV-PI双标记观察细胞凋亡情况。结果:(1)80μg/ml a STBM组作用4、16、32h时的细胞增殖抑制率分别为29.19±0.47、44.73±0.69、54.01±1.61;80μg/ml n STBM组作用4、16、32h的细胞增殖抑制率分别为57.15±0.70、64.35±0.89、71.67±0.63。a STBM、n STBM均能明显抑制HUVEC增殖,抑制作用呈浓度时间依赖性;n STBM对HUVECs的增殖抑制性明显高于a STBM,差异有统计学意义(P0.001)。RBC膜处理组对HUVECs增殖无明显影响,与空白组比较差异无统计学意义(P0.05)。(2)80μg/ml a STBM组的细胞早期凋亡率、晚期凋亡-坏死率分别为29.05%和7.46%。80μg/ml n STBM组分别为15.93%和30.31%。RBC膜处理组对HUVECs的凋亡无明显影响,与空白对照组相比,差异无统计学意义(P0.05)。a STBM、n STBM组均能引起HUVECs凋亡,n STBM作用HUVECs的晚期凋亡率高于a STBM组,两者有统计学意义(P0.001)。a STBM主要诱导HUVECs早期凋亡。结论:a STBM、n STBM对内皮细胞有抑制细胞增殖作用,a STBM主要以促进内皮细胞早期凋亡为主,而n STBM以内皮细胞晚期凋亡为主,n STBM对内皮细胞造成的损害强于a STBM。     

Soluble fms-like tyrosine kinase-1 in HIV infected pre-eclamptic South African Black women

Introduction

Hypertensive disorders of pregnancy are the commonest direct cause of maternal deaths in South Africa, 83% being attributed to pre-eclampsia. Elevated placental sFlt-1 levels are linked with angiogenic disruption and subsequent pre-eclampsia development. The impact of HIV infection on pre-eclampsia is controversial. Its effect on angiogenic imbalance in both normotensive and pre-eclamptic pregnancies remains unknown.

Methods

We examined the immunolocalisation of both membrane bound and soluble forms of Flt-1, within placentae of HIV negative and positive normotensive and pre-eclamptic pregnancies at term using immunohistochemistry and immuno-electron microscopy.

Results

Strong Flt-1 and sFlt-1 immunoreactivity was observed within endothelial, syncytio and cytotrophoblast cells. Subcellularly, gold particles were localised predominantly within the endoplasmic reticulum and mitochondria and occurring free within the cytoplasm. There was no significant effect of HIV on Flt-1 and sFlt-1 immunoexpression in both exchange and stem villi. A significant effect of type of pregnancy (normotensive vs pre-eclamptic) on Flt-1 and sFlt-1 immunoexpression (p = 0.003) within exchange rather than stem villi, indicated that the pre-eclamptic had elevated Flt-1 and sFlt-1 expressions compared to the normotensive pregnant women. There was no interaction between HIV and pregnancy type (normotensive vs pre-eclampsia) for Flt-1 and sFlt-1 expressions in both exchange and stem villi. A weak correlation of Flt-1 and sFlt-1 intensity between the exchange and stem villi was noted.

Discussion

Elevated immunoexpression of Flt-1 and sFlt-1 within trophoblasts suggests an autocrine mode of action on trophoblast invasion and differentiation thereby contributing to abnormal placentation with consequential endothelial dysfunction in pre-eclampsia.

Conclusion

Irrespective of the HIV status, placental Flt-1 and sFlt-1 expressions remain elevated in pre-eclampsia compared to normotensive pregnancies.     

The preeclampsia biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor: current knowledge, clinical implications and future application

Preeclampsia is a leading cause of maternal and fetal/neonatal morbidity and mortality worldwide. Currently there is no single reliable parameter for the diagnosis of preeclampsia and attention has turned towards identifying non-invasive testing methods, including Doppler sonography and blood-borne or urinary biomarkers in women who go on to develop preeclampsia. Biomarkers of angiogenesis are currently at the most advanced state of development for the diagnosis of preeclampsia. In this article we will highlight the diagnostic potential of the novel biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor and discuss the opportunities and challenges involved in bringing these preeclampsia biomarkers from bench to bedside.     

Increased plasma soluble fms-like tyrosine kinase 1 and endoglin levels in pregnancies complicated with preeclampsia

Background.?Increased maternal plasma levels of proinflammatory cytokines as well as the anti-angiogenic agents soluble fms-like tyrosine kinase 1 (sFlt-1) and endoglin (sEng) are associated with promoting vascular dysfunction leading to the maternal syndrome of preeclampsia.

Objective and method.?Nulliparous women complicated with preeclampsia (n = 29) and their corresponding controls (n = 29) delivering at the Enrique C. Sotomayor Obstetrics and Gynecology Hospital, Guayaquil-Ecuador were requested to participate in a study evaluating plasma levels of soluble anti-angiogenic factors (sFlt-1 and sEng) and pro-inflammatory cytokines: interleukin 6 (IL-6), interleukin 8 (IL-8), granulocyte colony stimulating factor (G-CSF), and tumor necrosis factor-alpha (TNF-α). Maternal and neonatal data were also assessed and compared among the study groups.

Results.?No significant differences in either maternal baseline or delivery characteristics were observed among the study groups. Compared with controls, preeclamptic women exhibited higher plasma levels of sFlt-1 (19.0 ± 15.1 vs. 12 ± 8.3 ng/mL) and of sEng (20.4 ± 9.9 vs.15.9 ± 9.4 ng/mL); respectively, p < 0.05. Women with severe disease displayed higher sFlt-1 and sEng levels when compared with mild ones (34.5 ± 11.6 vs. 9.5 ± 1.6 ng/mL, and 29.5 ± 9.0 vs. 14.8. ± 5.2 ng/mL, respectively; p < 0.001). In contrast, women with preeclampsia exhibited significant lower IL-8 and G-CSF levels compared with controls. No differences existed between either group in IL-6 levels or TNF-α.

Conclusion.?Consistent with previous reports, increased sFlt-1 and Eng levels in maternal plasma is consistent with vascular dysfunction found in gestations complicated with preeclampsia.     

Soluble fms-like tyrosine kinase-1 and soluble endoglin in HIV-associated preeclampsia

Objective

Preeclampsia is characterized by endothelial dysfunction combined with increased concentrations of sFlt1, which antagonizes the biological effects of VEGF and PlGF, and of sEng, which antagonizes TGFβ₁. This angiogenic imbalance may have a role in its etiology. This study evaluated the expression of VEGF, PlGF, sFlt1 and sEng amongst third trimester pregnancies in women with HIV-associated pre-eclampsia.

Method

Serum and placental tissue were obtained from 76 pregnancies in women who were normotensive and HIV negative (N−) or positive (N+), and in women who were pre-eclamptic and HIV negative (P−) or positive (P+). The serum and placental samples were quantitatively evaluated using ELISAs and RT-PCR respectively.

Results

Placental sFlt1 expression differed significantly between the N− and P− groups (p = 0.001). Similarly, sEng expression differed between the N− and P− groups (p = 0.001). No significant effect was shown between HIV status and pregnancy. Serum sFlt1 (p = 0.02) and sEng (p = 0.001) were up-regulated in the P− compared to the N− groups. Similarly, no significant effect was shown between HIV status and pregnancy. Both VEGF and PlGF did not differ significantly between groups. Notably, sEng expression was elevated in both placenta and serum, whilst placental sFlt1 differed from serum. A weak but significant correlation between serum and placental concentration for sFlt1, sEng and PlGF (r = 0.26, p = 0.031; r = 0.42, p < 0.001 and r = −0.3, p = 0.014) was observed.

Conclusions

This novel study demonstrates an up-regulation of serum sFlt1 and sEng in preeclamptic compared to normotensive groups irrespective of the HIV status of the pregnancy. This implicates a contributory role of sFlt1 and sEng in preeclampsia development. The serum reduction of sFlt1 and sEng within the HIV positive compared to HIV negative cohorts may imply a neutralization of the immune hyperreactivity of preeclampsia.     

子痫前期与sEng及sFlt-1的关系

子痫前期是导致孕产妇和围生儿死亡的主要原因之一,目前其发病机制尚未完全明确.近来研究发现,血液循环中过量的可溶性Endoglin(sEng)及可溶性血管内皮生长因子受体1(sFlt-1)是导致子痫前期患者出现高血压、蛋白尿、水肿等症状的两种重要的抗血管形成因子.sEng和sFlt-1由胎盘分泌后释放入血,通过不同的作用机制引起血管内皮损伤,导致子痫前期发生.sEng和sFlt-1不仅在子痫前期发病中起重要作用.并且在临床症状出现前妊娠妇女血清浓度就已明显升高.可作为筛选、预测及诊断子痫前期的重要指标.     

Placental growth factor and soluble fms-like tyrosine kinase-1 are useful markers for the prediction of preeclampsia but not for small for gestational age neonates: a longitudinal study

Objective

To determine maternal serum concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) longitudinally in normal pregnancies, pregnancies that developed preeclampsia and pregnancies that deliver a small for gestational age (SGA) infant, in order to evaluate them as markers for the prediction of preeclampsia.

Study design

In this case–control study we included 12 singleton pregnancies that developed preeclampsia and 104 randomly selected singleton normal pregnancies. Fourteen of the normal pregnancies gave birth to an SGA infant. Blood samples and ultrasonographic data were collected during the 1st, 2nd and 3rd trimesters of pregnancy.

Results

In preeclamptic pregnancies, PlGF (pg/mL) (median; inter-quartile range) was significantly lower in the 2nd (208; 84–339) (p = 0.035) and in the 3rd trimester (202; 109–284) (p = 0.002) while sFlt-1 was significantly higher only in the 3rd trimester (2521; 2101–3041) (p = 0.011) compared to normal pregnancies (PlGF 2nd: 311; 243–440, PlGF 3rd: 780; 472–1037, sFlt-1 3rd: 1616; 1186–2220). In pregnancies with SGA infants, PlGF and sFlt-1 did not differ significantly from normal pregnancies in any trimester. The sFlt-1 to PlGF ratio was significantly higher in preeclamptic pregnancies than in normal pregnancies, in both the 2nd and 3rd trimesters. The relative difference and the slope of PlGF concentration between 1st and 2nd trimester were significantly reduced in preeclampsia compared to normal pregnancies. A logistic regression model with predictors BMI, 2nd trimester Doppler PI and relative difference of PlGF from the 1st to the 2nd trimester gave 46% sensitivity and 99% specificity for the prediction of preeclampsia, with a very high negative predictive value of 98.3%.

Conclusions

Our study confirms that maternal serum PlGF concentration is significantly lower, at least after 20th week, while sFlt-1 concentration is significantly higher in 3rd trimester, in pregnancies destined to develop preeclampsia. Pregnancies that gave birth to SGA infants do not have altered angiogenic factor concentrations throughout pregnancy. The relative difference of PlGF from the 1st to the 2nd trimester, uterine artery Doppler PI in the 2nd trimester and BMI are the most powerful markers for the prediction of preeclampsia.     

Circulating free soluble fms-like tyrosine kinase-1 during late first trimester in relation with placental volume as a surrogate for trophoblastic production: a physiology study in low-risk cohort

Background: Data on first-trimester circulating soluble fms-like tyrosine kinase-1 (sFlt-1) and ischemic placental disease is limited and conflicting. This study aimed to study its physiology in relation to trophoblastic mass as the source of production.

Methods: Low-risk (representing normal placentation) women from 11 0/7 to 13 6/7 weeks’ gestation were prospectively enrolled. Selective measurement of serum free sFlt-1 using a new automated assay from 100 eligible subjects was analyzed with gestational age, maternal weight, fetal crown-rump length (CRL), and mean uterine artery Doppler pulsatility index (PI). Placental volume (surrogate for trophoblastic mass) was estimated using 3-dimensional ultrasound and was assessed for its association with serum free sFlt-1.

Results: There was no significant association between serum free sFlt-1 and placental volume in either arithmetic (r?=?0.053, p?=?0.600), logarithmic (r?=?0.005, p?=?0.963), or quartile (p?=?0.703) scale. There was a significant negative correlation between free sFlt-1 level and maternal weight (r=?0.213, p?=?0.033). No significant correlation was found between free sFlt-1 level and gestational age (r?=?0.007, p?=?0.947), CRL (r?=?0.027, p?=?0.788), and uterine artery Doppler mean PI (r?=?0.020, p?=?0.828).

Conclusions: Lack of correlation between circulating free sFlt-1 level and placental volume suggests that trophoblasts are not its major source during first trimester with presumably physiologic placentation.     

Interleukin-13 stimulates the secretion of vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 by human oviductal epithelial cells

OBJECTIVE: The aim of this study is to evaluate the effects of interleukin (IL)-13, a Th2 cytokine, on the production of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in human oviductal cells in vitro. STUDY DESIGN: Human oviductal epithelial cells (OECs) were isolated from five premenopausal patients. The secretion of VEGF(165) and sFlt-1 by cultured OECs in response to IL-13 was measured using an enzyme-linked immunosorbent assay. RESULTS: The secretion of VEGF(165) and sFlt-1 was detected in cultured OECs under untreated conditions. IL-13 enhanced the secretion of VEGF(165) and sFlt-1 by OECs in a dose-dependent manner. CONCLUSION: The present findings suggest that IL-13 is a regulatory factor of VEGF and sFlt-1 production in the human fallopian tubes. IL-13 in the local environment may stimulate oviductal vascular permeability by inducing the production of VEGF by oviductal cells. The modulation of VEGF secretion by IL-13 secreted by the peri-implantation embryo may contribute to the normal and pathological processes of human reproduction during the peri-implantation period.