Placental growth factor (PlGF) and sFlt-1 during pregnancy: physiology, assay and interest in preeclampsia
Édouard LecarpentierS. VieillefosseBassam HaddadThierry FournierMarie-Clémence LeguyJean GuibourdencheVassilis Tsatsaris
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The placental growth factor (PlGF) and its soluble receptor (sFlt-1) are circulating angiogenic factors. During pregnancy these factors are released by the placenta into the maternal circulation. Preeclampsia affects 2-7% of pregnant women according to their risk factors and is characterized by high blood pressure and the onset of de novo proteinuria in the second half of pregnancy. Alterations of the sFlt-1/PlGF ratio in preeclampsia correlate with the diagnosis and adverse outcomes, particularly when the disease presents prematurely (<34 weeks). These factors can be assayed in maternal blood and measuring the sFlt-1/PlGF ratio is now available. We propose in this work to update the knowledge of these two molecules, describe their roles and evolution during normal pregnancy and preeclampsia, and finally to focus on the available assays.<i>Background:</i> An imbalance between angiogenic and antiangiogenic factors plays a fundamental role in the pathogenesis of preeclampsia. Serum levels of placental growth factor (PLGF), a factor promoting angiogenesis, in patients with preeclampsia are significantly lower than in nonpreeclamptic pregnancies. This study was designed to answer the question whether the measurement of PLGF at the beginning of the second trimester might be a predictive factor for the appearance of preeclampsia. <i>Methods:</i> Serum samples of 61 women were collected between 15 and 18 weeks of pregnancy. PLGF levels were measured using a human PLGF ELISA and correlated with the outcomes of pregnancy. <i>Results:</i> 7 women (11.47%) developed preeclampsia during pregnancy. Their PLGF levels between 15 and 18 weeks of pregnancy were significantly lower (p < 0.001) compared to the nonpreeclamptic pregnancies. Using a PLGF level of 41.84 pg/ml as a cutoff, this test has a sensitivity of 0.87 and a specificity of 0.83. <i>Conclusion:</i> Women who will develop preeclampsia in the course of pregnancy already have a significantly lower expression of PLGF between 15 and 18 weeks of pregnancy compared to those who will not. This test offers new possibilities in the prediction of preeclampsia.
Pathogenesis
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Preeclampsia is a relatively common pregnancy-related disorder. Both maternal and fetal lives will be endangered if it proceeds unabated. Recently, the placenta-derived anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG), have attracted attention in the progression of preeclampsia. Here, we established a unique experimental model to test the role of sFLT1 in preeclampsia using a lentiviral vector-mediated placenta-specific expression system. The model mice showed hypertension and proteinuria during pregnancy, and the symptoms regressed after parturition. Intrauterine growth restriction was also observed. We further showed that pravastatin induced the VEGF-like angiogenic factor placental growth factor (PGF) and ameliorated the symptoms. We conclude that our experimental preeclamptic murine model phenocopies the human case, and the model identifies low-dose statins and PGF as candidates for preeclampsia treatment.
Intrauterine growth restriction
Placentation
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Preeclampsia is one of the most common and most serious complications of pregnancy and the management of this condition still challenges obstetricians. Despite intensive research the etiology of preeclampsia still remains unclear. At the beginning of the 2000s preeclampsia-related research was directed towards factors that influence angiogenesis. Most studies have been carried out on the placental growth factor and soluble fms-like tyrosine kinase-1. Most publications confirm the increased concentrations of antiangiogenic factors and decreased concentrations of proangiogenic factors in maternal blood samples in preeclampsia even before the onset of clinical symptoms. According to our current knowledge antiangiogenic proteins are responsible for the endothelial dysfunction in the symptomatic stage of the disease. Placental growth factor and soluble fms-like tyrosine kinase-1 may have important roles in the prediction and treatment of the disease. The point of care detection of placental growth factor and soluble fms-like tyrosine kinase-1 may be used to predict preeclampsia. Rapid tests are available to determine the serum levels of the two proteins. Removal of soluble fms-like tyrosine kinase-1 from maternal circulation is a potential treatment option for early onset preeclampsia. Orv. Hetil., 2014, 155(47), 1860–1866.
Etiology
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( Obstet Gynecol . 2021;137:72–81) Progress has occurred recently to predict and diagnose preeclampsia in pregnant women. Angiogenic and antiangiogenic biomarkers such as placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were recently examined. In addition these factors have been implemented clinically as predictive measurements of preeclampsia. This study aims to review and analyze sFlt-1, PlGF, and the sFLt-1/PlGF ratio and their ability to predict time to delivery and adverse outcomes in patients with preeclampsia.
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Fetal growth
Bench to bedside
Diagnostic biomarker
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Preeclampsia is a major complication of pregnancy and is associated with significant fetal and maternal morbidity and mortality. Timely prediction of preeclampsia facilitates referral of potential patients to an adequate tertiary center, which helps reduce adverse outcomes associated with the disease. Moreover, by accurately ruling out preeclampsia, patients can be discharged safely and relieved of anxiety. Numerous candidate biomarkers have been proposed for the diagnosis and prediction of preeclampsia. Among these, maternal circulating factors such as soluble FMS-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor, and placental growth factor (PlGF), an angiogenic factor, are considered the most promising. Measuring these factors as a ratio allows assessment of the angiogenic imbalance that characterizes incipient or overt preeclampsia. The sFlt-1/PlGF ratio increases before the onset of preeclampsia and thus may help predict the disease. The test is used as a predictive tool in several countries but not yet routinely performed in Japanese hospitals.
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( Am J Obstet Gynecol . 2020;222:259.e1–259.e11) There is a clear need for quantitative testing methods to determine which patients with signs of preeclampsia may be at heightened risk for adverse pregnancy outcomes. The altered angiogenic factor concentrations including placental growth factor (PlGF) have been found to be associated with preeclampsia and precede the onset of preeclampsia by several weeks. While previous studies have found encouraging evidence that PlGF concentrations may predict adverse pregnancy outcomes, the association between angiogenic factors and time to delivery (TTD) is still unclear. This study aimed to examine the relationship between TTD and PlGF in pregnant women with gestational age <35 weeks with signs of preeclampsia and to evaluate the performance of PlGF as a predictor for TTD.
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Preeclampsia is a devastating multisystem syndrome and is a major cause of maternal, fetal and neonatal morbidity and mortality.Angiogenic factors contribute to the molecular mechanisms of preeclampsia and its main phenotypes such as hypertension and proteinuria.Very recently, novel anti-angiogenic proteins including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and one pro-angiogenic protein placental growth factor (PlGF) have been found to be significantly abnormal several weeks preceding the onset of clinical signs and symptoms.Automatic immunoassays are being developed for sFlt-1 and PlGF.This article will summarize our current knowledge of these markers and their roles on predicting preeclampsia.
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Preeclampsia, diagnosed in about 5% of pregnancies, is defined as the presence of new-onset hypertension and proteinuria after 20 weeks' gestation. Placental vascular dysfunction has been shown to precede the onset of preeclampsia, causing an increase in placental secretion of an antiangiogenic factor (soluble fms-like tyrosine kinase 1; sFlt-1) and a decrease in secretion of an angiogenic factor (placental growth factor; PlGF). In an industry-supported study, investigators explored the clinical value of …
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