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.

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.

Association of first trimester serum level of placental growth factor (PlGF) and cervical length with onset of preterm labour

Background: Preterm labour (PTL) or premature labour is defined as one where labour starts before the 37th completed week.  The incidence of preterm birth is around 5-10% and it is the leading cause of perinatal morbidity and mortality. Diagnosis and treatment of PTL is challenging. However, owing to the availability of effective strategies for prevention of preterm birth, risk identification and early prediction is even more essential. This may provide opportunity for intervention and better obstetric care. Various biochemical markers were studied for prediction of preterm labour, but the sensitivity and specificity were found to be low. This study focuses on determining whether serum level of PlGF and ultrasound measure of cervical length at 10 – 14 weeks period of gestation can be used for early prediction of preterm labour.Methods: 296 antenatal women participated in this prospective observational study carried out from Dec 2015 to Sep 2017 at a tertiary care hospital. Serum level of PlGF was determined at 10-14 weeks. In the same sitting, cervical length was measured by transvaginal sonography. All these patients were followed up in antenatal OPD for monitoring the onset of preterm labour.Results: Incidence of preterm labour was 6.76 %. Maternal characteristics and obstetric factors were comparable in cases and controls. Serum PlGF level and cervical length values were lower in preterm labour group than term deliveries. But this result was not statistically significant.Conclusions: Lower levels of PlGF and cervical length were seen in preterm labour group, although it was not found to be statistically significant.

The value of combined detection of sFIt-1, PLGF and Survivin in the diagnosis of early-onset preeclampsia / 中国医师进修杂志

s] Objective To analyze the diagnostic value of combined detection of sFIt-1, PLGF and Survivin in early onset preeclampsia. Methods From January 2017 to January 2018, 100 patients with early-onset PE were selected as observation group and 100 healthy pregnant women as control group in Tangshan Maternal and Child health Hospital Gynecology and Obstetrics. The expression levels of sFIt-1, PLGF and Survivin in serum were detected by enzyme-linked immunosorbent assay (ELISA), and the diagnostic value of each index was analyzed separately and jointly. Results The levels of sFIt-1 in the observation group were significantly higher than those in the control group: (36.58 ± 18.34) μg/L vs. (28.43 ± 3.28) μg/L (P<0.05), and the levels of PLGF and Survivin in the observation group were significantly lower than those in the control group: (213.18 ± 48.23) ng/L vs. (398.17 ± 41.19) ng/L, (0.72 ± 0.29) μg/L vs. (1.43 ± 0.32) μg/L (P<0.05); 103 cases of positive sFIt-1, 108 cases of positive PLGF, 107 cases of positive Survivin, 121 cases of positive parallel combined diagnosis and 121 cases of positive series combined diagnosis were found. The sensitivity and negative predictive value of parallel combined diagnosis were significantly higher than those of individualized diagnosis (P<0.05), and the specificity and positive predictive value of series combined diagnosis were significantly higher than those of individualized diagnosis (P < 0.05). Conclusions The combined detection of sFIt-1, PLGF and Survivin in serum can effectively improve the diagnostic accuracy of early-onset preeclampsia and has high clinical value.

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.

Risk assessment for preeclampsia by biochemical and biophisycal markers at first trimester / Монголын Анагаах Ухаан

Introduction@#Preeclampsia, which affects about 2-8% of pregnancies, is major cause of maternal and perinatal morbidity and mortality, particularly in developing countries. In Mongolia, preeclampsia and eclampsia occurred among pregnancy complications about 25% in recent years. There is a percentage for a cause of maternal death was 17.7% in preeclampsia and eclampsia between 2012 and 2015 in Mongolia.</br> Effective prediction of preeclampsia can be achieved at 11-13 week’s gestation by combination of maternal characteristics, mean arterial pressure (MAP), uterine artery pulsatility index (UtA PI), maternal serum placental growth factor (PlGF), and pregnancy-associated plasma protein-A (PAPP-A).@*Goal@#To investigate plasma concentration of PIGF and PAPP-A, in pregnant women at 11-13+6 of gestation for screening of preeclampsia, To examine the performance of first-trimester screening for preeclampsia based on maternal characteristics, MAP, and mUt.A-PI.@*Materials and Methods @#The study conducted among 393 single pregnant women at 11-13+6 weeks, who were visiting antenatal care services, between March, 2015 and June, 2017. The prospective Cohort research method was used for this study. Written informed consent was obtained from all participants. Maternal plasma PAPP-A, PlGF were determined using Perkin Elmer kits by fluoroimmunoassay.</br> Measurement of MAP was by validated automated devices (HEM-7120, Оmron, Japan). MAP was calculated from the formula DP + 1/3*(SP-DP), where DP represents diastolic blood pressure and SP- systolic blood pressure. Trans-abdominal ultrasound (Voluson E8, GE, USA) examination was carried out for Ut.A-PI.@*Results@#In the study population, there were 66 (16.8%) cases that experienced preeclampsia and 327 (83.2%) cases that were unaffected by preeclampsia. The result showed that the mean concentration of PlGF was 38.6±19.6 pg/ml in PE group whereas the mean was 45.1±24.0 pg/ml in normal pregnant women. Level of PAPP-A was 366.1±195.3 mU/L in group with PE, 633.6±496.9 mU/L in group without preeclampsia. </br> The best Youden’s index and area under the curve (AUC) for MAP and mUt.A-PI were as a predictor of PE. It can be shown that the cutoff point for MAP was 89.5 mmHg (sensitivity-71.2%; specificity-75.5% J-0.467; AUC-0.792; P<0.001). The cutoff point of mUt.A-PI was 2.34 (sensitivity-33.3%; specificity-77.7% J-0.12; AUC-0.577; P<0.001).@*Conclusions@#The concentration of PIGF and PAPP-A in pregnant women with preeclampsia at 11-13+6 of gestation was lower than normal pregnant women. The detection risk of PE by MAP is more accurate than the mUtA-PI measurement.

A study in the correlation between vascular factors and plaque imaging morphology of coronary borderline lesions in patients with coronary heart disease / 中华急诊医学杂志

Objective To investigate the correlation between the levels of placenta growth factor (PLGF),soluble angiopoietin receptor-2 (sTie-2) and critical coronary artery plaque imaging morphology of coronary borderline lesions in patients with coronary heart disease (CHD).Methods In three consecutive years from April 2007 to September 2009,a cohort of 719 patients with borderline coronary lesions with stenosis in three main vessels with lumen diameter reduction varied all the way from more than 20％ to less than 70％ and with greater than 2.25 mm of the inner diameter were selected in this study from 4 teaching hospitals of tertiary class A in Beijing.These patients fell into three categories:unstable angina pectoris (UAP,n =292),stable angina pectoris (SAP,n =219) and coronary arteriosclerosis (AS,n =208).The vessels involved were analyzed using quantitative coronary angiography (QCA).Plasma levels of PLGF and sTie-2 were measured by using protein chip.The relationship between plasma levels of vascular factors,sTie-2,PLGF and coronary artery plaque imaging morphology among three groups were analyzed.Results (1) Plasma level of PLGF was 80.33 ng/L in the UAP group,which was significantly higher than 54.29 ng/L in the SAP group and 45.16 ng/L in AS group (both P ＜0.05).Plasma level of sTie-2 was 1353.06 ng/L in the UAP group,which was significantly higher than 1308.28 ng/L in the AS group (P =0.008).(2) There was significantly statistical differences in QCA between the SAP group and the UAP group as well as the AS group (both P ＜ 0.05) in terms of the minimal lumen diameter,diameter stenosis rate,minimal lumen cross-sectional area and cross-sectional area of stenosis.The plaque area in the UAP group was larger than that in the AS group (P =0.013).(3) The relationship between vascular factors and plaque imaging morphology was analyzed.There was significantly statistical difference in the involved lesions among the three groups (P ＜ 0.01).(4) There was a positive correlation between plasma level of PLGF and minimal lumen cross-sectional area (r =0.493,P =0.009).Conclusions The plasma levels of PLGF and sTie-2 reflect the level of neo-vascularization in the plaque,and could be taken as predictive factors for potential pathogenesis of coronary plaque.

The relationship of serum placental growth factor and carotid atherosclerosis in patients with type 2 diabetes mellitus / 中国糖尿病杂志

Objective To explore the relationship between serum placental growth factor (PLGF) and carotid atherosclerosis (CAS) in patients with type 2 diabetes mellitus (T2DM ). Methods Serum PLGF were determined by ELISA in 53 patients with T2DM ,who were divided into T2DM without carotid plague (T2DM group ,n= 27) and T2DM with carotid plague (T2DM + CAS group ,n= 26). Fasting plasma glucose (FPG) ,glycosylated hemoglobin A1c (HbA1c) and some other metabolic variables were also measured. The results were compared to those of 27 healthy controls (NC group). Results Serum PLGF levels were significantly higher in T2DM group and T2DM + CAS group than in NC group (P<0.01). T2DM+CAS group showed significantly higher serum levels of PLGF compared to that of T 2DM group(P<0.01).Correlation analysis showed that serum PLGF was positively correlated with TC ,LDL‐C , hsC‐RP and IL‐6 in T2DM patients (P<0.01). Similarly ,multiple regression analysis showed that LDL‐C and IL‐6 were the independent factors of serum PLGF level (P<0.05). Furthermore ,Serum PLGF was positively associated with carotid plague. Conclusion PLGF is positively related with chronic inflammation factors in T2DM patients. Serum PLGF may play an important role in the occurrence and development of carotid atherosclerosis and other macroangiopathy in T 2DM.

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.

Comparison of the effects of placental growth factor and vascular endothelial growth factor on acute myocardial infarction / 中华胸心血管外科杂志

Objective AMI is a prevalent global health condition.This study assessed the effects of PLGF and VEGF in a rat model of post-AMI.Methods Wistar rats underwent LAD ligation and injection of VEGF,PLGF,VEGF + PLGF,antiVEGFR1,anti-VEGFR2,anti-VEGFR1 + anti-VEGFR2,IgG2α,or saline,into the infarct border zone.We also set up a pseudo-operation group.Two weeks later,heart function was detected by hemodynamic and geometry,then the hearts were dis sected and HE stained.We assessed vW factor and α-SMA by immunohistochemistry and cardiomyocyte apoptosis rate by TUNEL.Results Rats in the VEGF + PLGF group performed significantly well in cardiac function,had weaker LV remodeling and less cardiomyocyte apoptosis.There were no obvious changes in VEGF group.The use of VEGFR1/VEGFR2 antibody didnt deteriorate the rat's cardiac function.More new-born arteries were seen in PLGF and VEGF + PLGF rats,and change wasnt found in other groups.Lastly,the most angiogenesis,the least left ventricular remodeling and the best heart function were observed in VEGF + PLGF group.Conclusion Earlier intervention with PLGF or VEGF + PLGF can improve heart function in rats with AMI; VEGF alone didnt improve heart function.VEGFR1/VEGFR2 antibody didnt aggravate the rat's heart function.This indicates that left ventricular and coronary remodeling may involve other factors.

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.

Therapeutic Effects of Tazarotene on Psoriasis and Its Potential Action Mechanism in Inflammatory Angiogenesis / 대한피부과학회지

BACKGROUND: Psoriasis is characterized by chronic recurrent erythematous skin plaques that exhibit epidermal hyperplasia, inflammatory cell accumulation and abnormalities of the papillary dermal vasculature. Psoriatic skin lesions show enlargement and increased tortuosity of cutaneous microvessels without formation of new vessel sprouts, that is, inflammatory angiogenesis. Placental growth factor (PlGF) and Tie-2 were reported to be up-regulated during inflammatory angiogenesis. Tazarotene is the first receptor-selective retinoid and its effects include normalizing keratinocyte differentiation, reducing keratinocyte proliferation and reducing inflammation. OBJECTIVE: Our study evaluated the clinical efficacy of topical tazarotene treatment and clarified histological changes and possible action mechanisms of this agent in respect of inflammatory angiogenesis. METHODS: We selected patients with symmetric psoriatic lesions and applied 0.1% tazarotene gel (Tazorac(R)) versus calcitriol 3 microgram/g gel (Silkis(R)) twice a day for 12 weeks with a right-left comparison. We grouped the patients with treatment modalities. Clinical efficacy, which was measured by the overall lesional assessment (OLA) scores, was assessed at each visit in 2 week' intervals until treatment closed. Skin biopsies were performed before the treatment started and again at 4 weeks and 12 weeks after treatment. Immunohistochemistry of PlGF, Tie-2 and factor-VIII was performed to elucidate the anti-angiogenetic effect of tazarotene. RESULTS: At the completion of 12 weeks of treatment, the OLA score of tazarotene-treated lesions was more reduced than that of calcitriol-treated lesions combined with phototherapy, it was more effective. Several histologic features such as epidermal hyperplasia, inflammatory cell infiltration and vessel dilation/tortousity were improved with decreased PlGF and Tie-2 expressions. CONCLUSION: These results indicate that tazarotene is an effective topical agent for psoriasis by blocking inflammatory angiogenesis.

Expression of Placenta Growth Factor mRNA Transcripts and Protein in Nasal Mucosa and Nasal Polyps

Placenta growth factor (PIGF) was originally described as a placenta produced homodimeric protein that shares substantial structural similarity with vascular endothelial growth factor (VEGF). It is becoming increasingly evident that PIGF may directly or indirectly modulate several key vascular events in various tissues. These include angiogenesis or vasculogenesis, vascular maturation and stabilization, vascular permeability, and endothelial cell survival. Inflammatory reaction in the nasal mucosa increases mucosal vascular permeability, resulting in edematous nasal mucosa with polypoid change. In this respect, PIGF may play a role in the formation of nasal polyp. In the present study we evaluated the expression of PIGF mRNA and protein in human inferior turbinate mucosa and nasal polyp. The expression and localization of PlGF mRNA and protein were investigated in the inferior turbinate mucosa and nasal polyps using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. These results showed that the mRNA transcripts and protein for PlGF are expressed in human turbinate mucosa and nasal polyps. Semiquantitative RT-PCR revealed that PIGF mRNA in nasal polyps increased in its expression level than that in nasal turbinate mucosa. Likewise, immunoblot analysis demonstrated a higher expression of PIGF protein in nasal polyp tissues, compared with that of the nasal turbinate mucosa. However, immunohistochemical findings revealed that PlGF is localized in the endothelial lining of blood vessels in the inferior turbinate mucosa, whereas it is expressed in the epithelial cells of nasal polyps. These results indicate that PlGF mRNA and protein are expressed in normal turbinate mucosa and nasal polyp. Further, based on the fact showing that the expression site of PIGF is different in both tissues, the action mechanism of PIGF may be different in human nasal mucosa and nasal polyp. That is, the PIGF may play a role in the physiological function of normal nasal mucosa, possibly the maintenance of blood vessel and in the pathogenesis of nasal polyp formation.

Expression and Localization of the PlGF mRNA in Preeclamptic Placentas / 대한산부인과학회잡지

OBJECTIVE: To identify and localize the Placenta Growth Factor (PlGF) mRNA in term placentas and to determine whether there are any differences in the expression of PlGF mRNA in the placentas between normal and preeclamptic pregnancy. METHODS: Northern blot and In situ hybridization with 5 cases of preeclamptic placentas and 8 cases of normal controls RESULTS: In Northern blot analysis and In situ hybridization, PlGF2 mRNA (1.7 kb) band was identified and showed significant decrease in density in preeclamptic placentas compared to that of normal controls. PlGF mRNA was mainly expressed in the syncytial membrane of villous trophoblast, and in the perivascular tissue surrounding the vasculature of stem villi. CONCLUSION: Decreased levels of PlGF mRNA in preeclamptic placentas could have some unfavorable influences on trophoblast and endothelial function, thereby may play a role to the pathogenesis of preeclampsia.

Gene Expression of Vascular Endothelial Growth Factor(VEGF) and Placental Growth Factor(PlGF) in Human Placenta / 대한산부인과학회잡지

OBJECTIVE: To determine whether gene expressions of VEGF and PlGF are different between the human placenta of normal and abnormal pregnancy. METHODS: Placenta was collected at each trimester of normal pregnancy, missed abortion, intrauterine growth retardation and pre-eclampsia. Total RNA was extracted from placenta. Reverse transcription-polymerase chain reaction(RT-PCR) was performed using VEGF and PlGF primer. RESULTS: VEGF121, VEGF165 and VEGF189 were identified in normal pregnancy and missed abortion. In two cases of four IUGR and one case of three pre-eclampsia, four of isoforms (VEGF121, VEGF145, VEGF165, and VEGF189) were identified. The intensity of signal was strongest for VEGF165 in all cases. PlGF131 and PlGF152 were identified in all cases. However, the signal intensities of VEGF121, VEGF165, VEGF189, PlGF131 and PlGF152 were not different according to the gestational age. They were also not different between normal pregnancy and abnormal pregnancy. CONCLUSION: VEGF and PlGF were not only expressed at placenta but also overexpressed in part of IUGR and pre-eclampsia. The results suggest that VEGF may play a role in the induction of angiogenesis of placenta in normal pregnancy and its production may be increased under the hypoxic condition.