Evaluation of angiogenic factors (PlGF and sFlt-1) in pre-eclampsia diagnosis / Avaliação dos fatores angiogênicos (PlGF e sFlt-1) no diagnóstico de pré-eclâmpsia

Abstract Objective: Recent observations support the hypothesis that an imbalance between angiogenic factors has a fundamental role in the pathogenesis of pre-eclampsia and is responsible for the clinical manifestations of the disease. The goal of the present study was to evaluate the sensitivity, specificity, and the best accuracy level of Soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in maternal serum and protein/creatinine ratio in urine sample to define the best cutoff point of these tests to discriminate between the patients with gestational hypertension and the patients with pre-eclampsia, to evaluate the possibility of using them as diagnostic methods. Methods: A prospective longitudinal study was performed, and blood samples were collected from 95 pregnant patients with hypertension to measure serum concentrations of biomarkers sFlt-1 and PlGF. Urine samples were collected for protein screening. Significance was set as p < 0.05. Results: The sFlt-1/PlGF ratio demonstrated a sensitivity of 57.5% and a specificity of 60% using 50.4 as a cutoff point. The test that showed the best accuracy in the diagnosis of pre-eclampsia was protein/creatinine ratio, with a sensitivity of 78.9% and a specificity of 70% using 0.4 as a cutoff point and showing an area under the receiver operating characteristic curve of 0.80 (p < 0.001). Conclusion: No studied laboratory test proved to be fairly accurate for the diagnosis of pre-eclampsia, except for the protein/creatinine ratio. The evidence is insufficient to recommend biomarkers sFlt-1 and PlGF to be used for the diagnosis of pre-eclampsia.

Resumo Objetivo: Pesquisas recentes sustentam a hipótese de que um desequilíbrio entre fatores angiogênicos desempenhe um papel fundamental na patogênese da pré-eclâmpsia e seja responsável pelas manifestações clínicas da doença. O objetivo do presente estudo foi avaliar a sensibilidade, a especificidade e o nível de melhor acurácia do Fator semelhante a tirosina quinase 1 (sFlt-1), Fator de crescimento placentário (PlGF), e relação sFlt-1/PlGF no soro materno e relação proteína/creatinina em amostra de urina e definir o melhor ponto de corte desses testes para distinguir pacientes com hipertensão gestacional daquelas com pré-eclâmpsia, a fim de avaliar a possibilidade de utilizá-los como métodos diagnósticos. Métodos: Foi realizado um estudo prospectivo longitudinal e foram coletadas amostras de sangue de 95 gestantes com hipertensão arterial para dosar as concentrações séricas dos biomarcadores sFlt-1 e PlGF. Amostras de urina foram coletadas para pesquisa de proteinúria. Foram consideradas significativas as diferenças com p < 0,05. Resultados: A relação sFlt-1/PlGF demonstrou sensibilidade de 57,5% e especificidade de 60% utilizando 50,4 como ponto de corte. O teste que apresentou a melhor acurácia no diagnóstico de pré-eclâmpsia foi a relação proteína/creatinina, com sensibilidade de 78,9% e especificidade de 70%, utilizando 0,4 como ponto de corte e demostrando uma área sob a curva receiver operating characteristic (ROC, na sigla em inglês) de 0,80 (p < 0,001). Conclusão: Nenhum método de rastreamento isolado se mostrou com boa acurácia para o diagnóstico de pré-eclâmpsia, exceto a relação proteína/creatinina. As evidências são insuficientes para recomendar os biomarcadores sFlt-1 e PlGF como diagnóstico de pré-eclâmpsia.

Ethanolic extract of Moringa oleifera leaves improve inflammation, angiogenesis, and blood pressure in rat model of preeclampsia

The aim of this study is to investigate the effect of the ethanolic extract of Moringa oleifera leaves (EMOL) to improveinflammation, angiogenesis, and blood pressure by evaluating the serum level of IL-17, soluble vascular endothelialgrowth factor receptor 1 (sFlt-1), and blood pressure in a rat model of preeclampsia (PE). The rat model of PE wasinduced with Nω-nitro-L-arginine methyl ester (L-NAME) of 50 mg/kg body weight (b.w) on day 12–18 of gestation.On day 5 of gestation, three groups are given EMOL dose of 50,100, and 200 mg/kg b.w, and one group administeredaspirin of 1.35 mg/200 g b.w. Blood pressure was measurement on days 0, 11, and 19 of gestation. On day 20 ofgestation, the rats were sacrificed, and serum parameters were analyzed. There is a significant difference in the serumlevel of IL-17 in all of the groups (p ˂ 0.05). EMOL doses of 50 and 100 mg/kg b.w prevent an increase in the serumlevel of IL-17 better than low-dose aspirin (p ˂ 0.05). There was a tendency decrease in sFlt-1 serum levels withEMOL doses of 50 and 100 mg/kg b.w, but statistically there are no significant differences (p > 0.05). All the doses ofEMOL have the same effect as low-dose aspirin to prevent blood pressure increase in the rat model of PE (p ˂ 0.05).

Comparative study of sFlt-1/Plgf ratio with uterine artery doppler indices in prediction of preeclampsia at 22-24 weeks period of gestation

Background: Hypertensive disorders like pre-eclampsia along with hemorrhage and infection, contributes greatly to maternal morbidity and mortality. Various pro and antiangiogenic factors like sFlt-1 and Plgf have been linked to the etiopathogenesis of placental vascular disease and their combination with uterine artery doppler studies may improve the prediction accuracy. Present study was conducted to analyze sFlt-1/Plgf ratio and uterine artery doppler indices among high risk patients and to compare these in prediction of preeclampsia.Methods: A prospective observational study was conducted from September 2017 to February 2019 in which 100 patients giving consent and satisfying inclusion criteria were evaluated for various risk factors and were subjected to sFlt-1/Plgf ratio test and uterine artery doppler study at 22-24 weeks period of gestation. They were followed up and maternal outcome was analysed.Results: Among the cohort of 100 women with high risk factors, 35% of the study participants developed pre-eclampsia. Using sFlt-1/Plgf ratio 40% of them were screened positive for pre-eclampsia. This percentage of screened positive was 40%, 43%, and 53% using uterine artery RI, PI, and SD respectively. sFlt-1/Plgf was found to have a sensitivity of 91.4% and specificity of 87.7%. ROC curve analysis showed highest area under curve (AUC) for sFlt-1/Plgf (0.858).Conclusions: sFlt-1/Plgf ratio was found to be a better predictable biomarker than uterine artery Doppler indices in prediction of pre-eclampsia at 22-24 weeks period of gestation.

Análise de impacto orçamentário do uso da razão dos testes sFlt-1: PlGF na exclusão de pré-eclâmpsia em mulheres com suspeita clínica na perspectiva do sistema de saúde suplementar / Budget impact analysis of sFlt-1/PlGF ratio to help rule-out pre-eclampsia in women presenting with clinical suspected in the private healthcare system perspective in Brazil

Objetivo: O objetivo do estudo foi avaliar o impacto econômico da incorporação da razão dos testes tirosina quinase-1 solúvel (sFlt-1):fator de crescimento placentário (PlGF) no auxílio da exclusão da pré-eclâmpsia na perspectiva do Sistema de Saúde Suplementar do Brasil (SSS). Métodos: Foi desenvolvido um modelo de decisão com o intuito de simular as decisões clínicas do manejo das pacientes com suspeita de pré-eclâmpsia entre a 24ª semana e a 36ª semana + 6 dias de gestação utilizando a razão dos testes sFlt-1:PlGF em comparação com cenário sem o teste. Os dados clínicos utilizados no modelo foram derivados do estudo PROGNOSIS. A análise incluiu apenas custos diretos que foram baseados na Tabela CBHPM (Classificação Brasileira Hierarquizada de Procedimentos Médicos) e na Tabela CMED PF 18% (Câmara de Regulação do Mercado de Medicamentos). Uma análise de sensibilidade univariada foi conduzida com variação de 15% dos parâmetros. Resultados: A razão dos testes sFlt-1:PlGF apresentou um potencial de economia de -R$ 4.532,04 por paciente comparado ao cenário sem teste. Considerando a incorporação no SSS, a razão dos testes sFlt-1:PlGF pode promover uma economia de -R$ 6.375.865,68 em 2021 e um acumulado de -R$ 136.495.533,87 em cinco anos. Conclusão: O uso da razão sFlt-1:PlGF no auxílio da exclusão da pré-eclâmpsia tem potencial de melhorar as decisões clínicas e, consequentemente, evitar hospitalizações desnecessárias. A incorporação do teste pode promover uma economia substancial para o sistema de saúde suplementar

Objective: The aim of this study was to evaluate the economic impact of the incorporation of the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test in the private healthcare system in Brazil (SSS). Methods: A decision model was developed in order to simulate the clinical decisions of the management of women with suspected pre-eclampsia between 24 weeks and 36 weeks plus 6 days with sFlt-1:PlGF ratio test, compared with no test scenario. The clinical data used in the model were derived from PROGNOSIS study. The analysis included only direct costs that were based on CBHPM (Classificação Brasileira Hierarquizada de Procedimentos Médicos) and CMED PF 18% (Câmara de Regulação do Mercado de Medicamentos). A univariate sensitivity analysis was conducted with a variation of 15%. Results: The sFlt-1:PlGF ratio test has the potential to save -R$ 4.532,04 per patient compared to no test scenario. Considering the incorporation of the test in SSS, the sFlt1:PlGF ratio test can promote an economy of -R$ 6.375.865,68 in 2021 and -R$ 136.495.533,87 in accumulated five years of. Conclusion: The use of sFlt-1:PlGF ratio test to help rule-out pre-eclampsia has the potential to improve clinical decision and therefore to reduce unnecessary hospitalizations. The incorporation of the test can promote a substantial saving to the private healthcare system.

Correlación de los valores de sFlt-1, PlGF y su cociente en preeclampsia con criterios de severidad en una Unidad de Cuidados Intensivos / Correlation of the values of sFlt-1, PlGF and its precilampsy court with severity criteria in an Intensive Care Unit / Correlação dos valores de sFlt-1, PlGF e seu coeficiente em preeclampsia com critérios de gravidade em uma Unidade de Terapia Intensiva

Resumen: Introducción: La detección del desequilibrio entre los factores proangiogénicos/antiangiogénico (sFlt-1, PlGF, cociente sFlt-1/PlGF) en la sangre materna son herramientas de pronóstico y diagnóstico en preeclampsia. Objetivo: Determinar la correlación entre los valores sanguíneos de sFlt-1, PlGF, cociente sFlt-1/PlGF y las complicaciones en mujeres con preeclampsia severa. Material y métodos: Se estudiaron a mujeres que ingresaron a la UCI con diagnóstico de preeclampsia con criterios de severidad y se determinaron las variables clínicas y de laboratorio. Las concentraciones séricas de sFlt-1 y PlGF se realizaron con un equipo automático KRYPTOR compact Plus. Resultados: Encontramos que 33.3% fue preeclampsia temprana y 66.7% tardía. Los criterios de severidad fueron: 66.7% crisis hipertensiva y 33.3% encefalopatía hipertensiva. Existió una correlación negativa entre los valores de sFlt-1 y urea, creatinina, proteínas de orina en 24 horas, presión sistólica (TAS) y presión diastólica (TAD). La correlación fue pobre y no fue estadísticamente significativa. Existió una correlación positiva y estadísticamente significativa para ácido úrico. Existió una correlación negativa entre los valores de PlGF en TAS, TAD. No existió correlación entre los valores cociente sFlt-1/PlGF y las variables medidas como TAS, TAD. Conclusiones: Este estudio confirma que es posible identificar un desbalance angiogénico en mujeres con preeclampsia severa. Sin embargo, los marcadores angiogénicos no presentaron una correlación estadísticamente significativa con respecto a las variables clínicas y bioquímicas de preeclampsia en la Unidad de Cuidados Intensivos.

Abstract: Introduction: The detection of the imbalance between proangiogenic/antiangiogenic factors (sFlt-1, PlGF, sFlt-1/PlGF ratio), in maternal blood are prognostic and diagnostic tools in preeclampsia. Objective: To determine the correlation between blood values of (sFlt-1, PlGF, sFlt-1/PlGF ratio) and complications in women with severe preeclampsia. Material and methods: Women who were admitted to the ICU with a diagnosis of preeclampsia with severity criteria were studied, clinical and laboratory variables were determined. Serum concentrations of sFlt-1, PLGF were performed with a KRYPTOR compact Plus automatic equipment. Results: 33.3% were early preeclampsia and 66.7% late. The severity criteria occurred with 66.7% with hypertensive crisis and 33.3% with hypertensive encephalopathy. There was a negative correlation between the values of sFlt-1 and urea, creatinine, urine proteins in 24 hours, systolic pressure (ASD), diastolic pressure (ADT). The correlation was poor and not statistically significant. There was a positive and statistically significant correlation for uric acid. There was a negative correlation between PlGF values in TAS, TAD. There was no correlation between the sFlt-1/PlGF quotient values and the variables measured as TAS, TAD. Conclusions: This study confirms that it is possible to identify an angiogenic imbalance in women with severe preeclampsia. However, the angiogenic markers did not show a statistically significant correlation, with respect to the clinical and biochemical variables of preeclampsia in the Intensive Care Unit.

Resumo: Introdução: A detecção de desequilíbrio entre fatores pró-angiogênicos/antiangiogênicos (sFlt-1, PlGF, coeficiente sFlt-1/PlGF) no sangue materno são ferramentas de prognóstico e diagnóstico na pré-eclâmpsia. Objetivo: Determinar a correlação entre os valores sanguíneos de (sFlt-1, PlGF, coeficiente sFlt-1/PlGF) e complicações em mulheres com pré-eclâmpsia grave. Material e métodos: Foram estudadas mulheres admitidas na UTI com diagnóstico de pré-eclâmpsia com critérios de gravidade, determinou-se variáveis clínicas e laboratoriais. As concentrações séricas de sFlt-1, PLGF foram realizadas com um equipamento automático KRYPTOR compact Plus. Resultados: 33.3% eram pré-eclâmpsia precoce e 66.7% tardia. Os critérios de gravidade ocorreram com 66.7% com crise hipertensiva e 33.3% com encefalopatia hipertensiva. Houve correlação negativa entre os valores de sFlt-1 e uréia, creatinina, proteínas da urina em 24 horas, pressão sistólica (PAS) e pressão diastólica (PAD). A correlação foi ruim e estatisticamente não significante. Houve uma correlação positiva e estatisticamente significante para o ácido úrico. Encontrou-se uma correlação negativa entre os valores de PLGF no TAS, TAD. Não houve correlação entre os valores do quociente sFlt-1/PlGF e as variáveis medidas como PAS e PAD. Conclusões: Este estudo confirma que é possível identificar um desequilíbrio angiogênico em mulheres com pré-eclâmpsia grave. No entanto, os marcadores angiogênicos não apresentaram correlação estatisticamente significante com relação às variáveis clínicas e bioquímicas da pré-eclâmpsia na unidade de terapia intensiva.

Levels of molecular angiogenic and antiangiogenic in pregnant women with risk of preeclampsia

Background: Angiogenic and antiangiogenic imbalances play a major role in the pathogenesis of preeclampsia. Increased production of sFlt-1 by the placenta causes free circulating PIGF and VEGF concentrations to lower because it is bound by sFlt-1. Measuring levels of angiogenic and antiangiogenic proteins as biomarkers indicates placental dysfunction and distinguishes preeclampsia from other disorders. This study aims to analyze the levels of angiogenic and antiangiogenic molecules in pregnant women at risk for preeclampsia.Methods: The study with a cross-sectional design was carried out in 11-15 weeks gestational age whom had a risk of preeclampsia with 30 samples in primary health care starting April-August 2018. Blood serum was measured by molecular levels of VEGF, PlGF, sFlt-1, and sFlt-1/PlGF ratio using the ELISA method. Data analysis used Pearson product moment test.Results: The mean of VEGF levels are 15.5±21.6, PlGF 89.7±55.5, sFlt-1 11519.4±5126.0 and the ratio sFlt-1/PlGF 166.7±102.1. Correlation value of risk factors for preeclampsia with molecular levels of VEGF r= -0.05; p = 0.76, PlGF r= -0.21; p = 0.26, sFlt r= 0.01; p =0.99 and ratio sFlt-1/PlGF r = 0.10; p = 0.58.Conclusions: The higher the total score of preeclampsia risk factor, the lower the molecular level of VEGF and PlGF is. Moreover, the higher the total score of preeclampsia risk factor, the higher the molecular level sFlt-1 and the sFlt-1/PlGF ratio is. There are no significant correlation between total score of preeclampsia risk factor and levels of molecule VEGF, PlGF, sFlt-1 and sFlt-1/PlGF ratio.

The predictive value of sFlt-1/PIGF ratio in high risk patients for the development of preeclampsia

Background: Hypertensive disorders of pregnancy constitute a major cause of maternal morbidity and mortality. Pre-eclampsia/eclampsia ranks second only to haemorrhage as a specific, direct cause of maternal mortality. A number of markers have been under study for the early detection of this disease. The study aims to evaluate the predictive value of sFlt-1/PlGF ratio for preeclampsia.Methods: This study was conducted in the Department of Gynaecology and Obstetrics of ASCOMS hospital, Jammu for a period of 6 months from Jan 2019 to June 2019. 50 antenatal patients attending the outpatient department with risk factors for developing preeclampsia were enrolled in the study. Their sFlT-1/PIGF ratio was determined at gestational age of 20 weeks to 37 weeks and its predictive value was evaluated.Results: In the present study, 8 patients developed preeclampsia subsequently. The mean sFlt-1/PIGF ratio values were significantly higher in the patients who developed preeclampsia (73.5) than who did not develop the disease (26.07). The positive predictive value at 1 week was 41.66% and negative predictive value was 100%. At 4 weeks, positive predictive value was 66.66% and negative predictive value was 100%.Conclusions: The present study suggests sFlt-1/PIGF ratio values are useful marker was a predictor of preeclampsia and values >38 were associated with preeclampsia. It is more useful in ruling out preeclampsia than ruling in the disease.

Therapeutic effect of al-Quran murattal on anxiety, sFlt-1, PIGF and sFlt-1/PIGF ratio in pregnant women with risk of preeclampsia

Background: Pregnancy was a critical period. This study aimed to examine the effect of murattal al-Quran therapy on the level of anxiety, sFlt-1, and PIGF level in pregnant women with preeclampsia risk.Methods: A quasi-experimental study was conducted in February, 2018. Ten participants received routine midwifery care were combined with murattal of the Qur'an therapy, the rests as control group. Variables were measured at pre and post 12 interventions. Interviews were conducted after the intervention.Results: There was a mean difference of anxiety of 5.250 (SD of 11.021, 95% CI: 0.092-10,408, p-0.046), sFlt-1 p=0.411, PIGF p=0.002, sFlt-1/PIGF ratio p=0.001.Conclusions: This study found a decrease in the level of anxiety, increase score of PIGF and decrease of sFlt-1/PIGF ratio among pregnant women with the risk of preeclampsia who received routine midwifery care plus al-Quran Murattal therapy.

The predictive value of sFlt-1 combined with extravascular lung water index in severe pneumonia patients with acute respiratory distress syndrome complicated with septic shock / 中华急诊医学杂志

Objective To evaluate the prognosis value of plasma soluble vascular endothelial growth factor receptor (sFlt-1) combined with extravascular lung water index (EVLWI) in acute respiratory distress syndrome (ARDS) complicated with septic shock caused by severe pneumonia. Methods A retrospective analysis was conducted in Respiratory Intensive Care Unit of the Affiliated Zhengzhou Central Hospital of Zhengzhou University from January 2015 to July 2017. The study included 52 severe pneumonia patients with ARDS complicated with septic shock, who was performed by measurement of pulse index continuous cardiac output (PICCO) and survived more than 3 days after admission. According to the 28-day mortality, these patients were divided into the survival group (31 cases) and the death group (21 cases). PICCO was used to record the EVLWI level. The plasma level of sFlt-1 was measured by enzyme-linked immunosorbent assay (ELISA). Acute physiology and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score were calculated. Independent risk factors were analyzed by multiple logistic regression. Correlation analysis between plasma sFlt-1 and EVLWI and APACHE II values was performed on the 1st, 2nd and 3rd day after admission. Receiver operating characteristic curve (ROC) was calculated, and the prognostic value of each parameter was assessed. Results The blood lactate, APACHE II score and SOFA score in the death group were significantly higher than those in the survival group at RICU admission (P<0.05), and the length of RICU stay was significantly shorter than that in the survival group (P<0.05), while differences in other clinical characteristics between the two groups were not statistically significant. The levels of EVLWI, sFlt-1 and blood lactate, APACHE II score and SOFA score in the death group were significantly higher than those in the survival group on the 1st, 2nd and 3rd day (all P<0.05), whereas the PaO2/FiO2 was significantly lower than that of the survival group on the 2nd and 3rd day (all P<0.05). Logistic regression analysis showed that sflt-1 level and EVLWI were significantly related with the patient mortality. The levels of sFlt-1 on day 1, 2 and 3 after RICU admission were positively related to EVLWI and APACHE II score (all P<0.01). The sensitivity and specificity of sFlt-1 combined with EVLWI in prognosis evaluation were 89.7％, 78.2％ and 86.3％, 75.7％, respectively. The AUC of sFlt-1 combined with EVLWI was 0.875 and 0.856 on the 1st and 3rd day, respectively (all P<0.01), which had a better prognostic value than each of them. Conclusions SFlt-1 could be used as a biomarker of mortality for severe pneumonia patients with ARDS complicated with septic shock. The combination of sFlt-1 and EVLWI might be important in early prediction of the prognosis of the 28-day mortality in patients with ARDS complicated with septic shock caused by severe pneumonia.

Experimental study of regulatory effect of hydrogen sulfide on sFlt-1 production in adipocytes through ADAM17 / 中华内分泌代谢杂志

Objective To study the effect of hydrogen sulfide on the production of soluble fms-like tyrosine kinase 1 (sFlt-1) through a distintegrin and metalloproteinase 17 (ADAM17) in adipocytes. Methods 3T3-L1 cells were cultured and induced to differentiate into adipocytes, then treated with different doses of sodium hydrogen sulfide (NaHS), L-cysteine or transfected with cystathionine-γ-lyase ( CSE) siRNA, ADAM17 siRNA or treated with ADAM17 inhibitor, monoclonal antibody. 24 hours after treatment, the expression of ADAM17, CSE, and the production of sFlt-1 were determined. Results After the treatment of 10, 25, 50 nmol/L NaHS or 0. 5, 1. 0, 2. 0 μmol/L L-cysteine, the expression of ADAM17 and the production of sFlt-1 in adipocytes were significantly decreased, the higher dose of L-cysteine and sFlt-1, the lower expression of ADAM17 and the production of sFlt-1; the effect of 2.0 μmol/L L-cysteine decreasing the expression of ADAM17 and the production of sFlt-1 were reversed by transfection of CSE siRNA; after the transfection of ADAM17 siRNA and treatment of ADAM17 inhibitor or monoclonal antibody, the production of sFlt-1 in adipocytes were significantly decreased. Conclusion Hydrogen sulfide can reduce the production of sFlt-1 in adipocytes by downregulating the expression of ADAM17.

Diagnóstico de preeclampsia: antiangiogénesis, el nuevo estándar / Diagnosis of preeclampsia: Antiangiogenesis, the new standard

El reciente valor que han tomado los factores antiangiogénicos en la fisiopatología de la preeclampsia y por ello en el entendimiento de las manifestaciones multisistémicas de esta enfermedad nos está acercando a la aplicación clínica de los valores laboratoriales, tanto para el diagnóstico, valoración de gravedad y predicción o descarte de la preeclampsia. Revisaremos brevemente algunos alcances recientemente propuestos para la aplicación clínica.

The recent importance of antiangiogenic factors in the pathophysiology of preeclampsia and in the understanding of the multisystem manifestations of this disease is bringing closer the clinical application of laboratory values for the diagnosis, assessment of severity and prediction of preeclampsia. We will briefly review some recent examples in clinical application.

Expression of soluble vascular endothelial growth factor receptor-1 and placental growth factor in fetal growth restriction cases and intervention effect of tetramethylpyrazine

OBJECTIVE@#To investigate the expression of soluble vascular endothelial growth factor receptor-1 (sFlt-1) and placental growth factor (PLGF) in the fetal growth restriction (FGR) cases and the intervention mechanism of tetramethylpyrazine.@*METHODS@#A total of 60 fetal growth restriction cases that admitted to our hospital were randomly divided into ligustrazine intervention group (group A) and nutritional support group (group B). A total of 50 healthy pregnant women were also enrolled as control group (group C). Expression level of maternal serum sFlt1, PLGF and fetal growth parameters including HC, AC, FL, BPD, EFW as well as placenta PLGF, sFlt-1 mRNA expression were recorded and compared among the three groups. A total of 15 SD rats were selected and were divided into three groups, TMP group, alcohol and tobacco group and blank control group. Three groups of rats were dissected on the twentieth day of gestation.@*RESULTS@#Expression level of sFlt-1 and PLGF in group A was not significantly different from that of group C (P>0.05); but significant difference in SFlt1 and PLGF expression level was observed between group C and group B (P0.05). There was significant difference in PLGF between FGR group with treatment and FGR group without treatment or control group (P<0.01).@*CONCLUSIONS@#PLGF level is decreased and sFlt-1 increased in patients suffered from fetal growth restriction, and FGR rats show increased sFlt-1 and decreased PLGF, thus they can be indicator of the fetal growth restriction. Ligustrazine can effectively improve sFlt-1, PLGF expression level in fetal growth restriction cases, which can be used as treatment for FGR.

Sildenafil Inhibits Advanced Glycation End Products-induced sFlt-1 Release Through Upregulation of Heme Oxygenase-1

OBJECTIVES: We examined the effect of sildenafil citrate on advanced glycation end products (AGEs)-induced soluble fms-like tyrosine kinase 1 (sFlt-1) release in JEG-3 choriocarcinoma cells. METHODS: Cells were incubated with control bovine serum albumin (BSA) or AGEs-BSA, and expression of sFlt-1 mRNA and protein release was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. AGEs-BSA increased sFlt-1 mRNA expression and protein release in a dose-dependent manner. RESULTS: Sildenafil citrate suppressed sFlt-1 mRNA expression and protein release in cells treated with AGEs-BSA in a dose-dependent manner. Likewise, it inhibited the increase of reactive oxygen species (ROS) production and NF-kappaB activity in these cells. Cobalt protoporphyrin (CoPP) and bilirubin also inhibited sFlt-1 release and ROS production in cells treated with AGEs-BSA, whereas zinc protoporphyrin IX (ZnPP IX) antagonized the effect of sildenafil citrate. In cells transfected with the heme oxygenase-1 (HO-1) siRNA, sildenafil citrate failed to inhibit the sFlt-1 release and ROS production. CONCLUSION: These results strongly suggest that sildenafil citrate inhibits sFlt-1 release and ROS production in cells treated with AGEs-BSA through upregulation of the HO-1 expression in JEG-3 cells.

Reduced Number of Endothelial Progenitor Colony-Forming Units in Patients with Preeclampsia

PURPOSE: Endothelial progenitor cells (EPCs), which mediates neovascularization of uterine endometrium may be involved in the neovascularization in the utero-placental circulation. Low numbers of endothelial progenitor colony-forming unit (CFU) in culture are predictive biomarker of vascular disease. The aim of the present study was to evaluate whether the number of CFU in preeclampsia differed from that in normal pregnancy. MATERIALS AND METHODS: Women with singleton normal (n=26) or preeclamptic (n=20) pregnancies were studied during the third trimester. The number of EPCs was quantified by CFU methodology. Plasma levels of angiogenic factors, vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) were determined by enzyme-linked immunoassay. RESULTS: CFU numbers were significantly decreased in the preeclamptic patients compared with the controls (median, 3; range 1-12 vs. 31; 3-81 CFU/well, P<0.001). A majority of the cells comprising individual colonies were positive for endothelial characteristics (Ulex europaeus lectin staining and acetylated low-density lipoprotein uptake). Plasma levels of the sFlt-1 were highly elevated (P<0.001) in patient with preeclampsia compared to controls, whereas PlGF were highly reduced (P=0.004), but these factors did not associate with CFU numbers. CONCLUSION: Our results suggest that reduced numbers of CFU obtained from maternal peripheral blood may contribute to the development of preeclampsia.

The Levels of Circulating Vascular Endothelial Growth Factor and Soluble Flt-1 in Pregnancies Complicated by Preeclampsia

To evaluate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of preeclampsia, we measured total VEGF, free VEGF and soluble Flt-1 (sFlt-1) concentrations and determined their relationships. Maternal serum samples were collected from 20 patients with preeclampsia and 20 normotensive women with uncomplicated pregnancies matched with the patients with preeclampsia for gestational age and parity. The serum concentrations of total VEGF (2.39+/-0.75 vs. 0.28+/-0.14) and sFlt-1 (934.5+/-235.5 vs. 298.0+/-161.2) were significantly increased in the patients with preeclampsia compared to the women with uncomplicated pregnancies. However the serum concentration of free VEGF (21.5+/-6.3 vs. 134.0+/-16.3) was lower in patients with preeclampsia. There was a positive correlation between the serum concentrations of total VEGF and sFlt-1 with systolic and diastolic blood pressure, respectively. There was a negative correlation between the serum concentration of free VEGF and systolic and diastolic blood pressure. There was a strong negative correlation between free VEGF and sFlt-1 concentrations. In conclusion, we found VEGF and sFlt-1 were related to the pathogenesis of preeclampsia. Although reduced concentrations of free VEGF might interfere with endothelial cell function and survival, further studies are required to clarify its specific role in the pathogenesis of preeclampsia.

Free vascular endothelial growth factor and its soluble receptor in peritoneal fluid from endometriosis patients / 第三军医大学学报

Objective To better understand the regulation of the soluble receptor of vascular endothelial growth factor (VEGF), s-VEGFR-1 (or soluble fms-like tyrosine kinase, SFlt-1), in angiogenetic process in endometriosis. Methods Levels of free VEGF and s-VEGFR-1 were measured by enzyme-linked immunosorbent assay (ELISA) in peritoneal fluid from 28 subjects with surgically confirmed endometriosis, and 10 controls with no clinical evidence of the disease and other diseases. Meanwhile, we calculated a VEGF activity index by means of the ratio VEGF/s-VEGFR-1. Results We found higher VEGF concentration in endometriotic lesions than controls (P0.05). VEGF activity index in controls, stage Ⅰ-Ⅱ and stages Ⅲ-Ⅳ of endometriosis was 0.310, 0.276 and 0.273, respectively. VEGF and s-VEGFR-1 concentration were also higher in proliferative phase than in secretory phase in endometriotic lesions (P