sFlt-1 Levels Research Articles

To the question of the clinical predictive value of the sFlt-1:PlGF ratio is related to the placental dysfunction

The objective: to evaluate the clinical and prognostic value and meaning of the ratio of the anti-angiogenic factor of soluble fms-like tyrosine kinase-1 (sFlt-1) to the angiogenic factor of the placental growth factor (PlGF) in the dynamics of pregnancy as markers of various variants of placental dysfunction. Materials and methods. A retrospective cohort study of 40 pregnant women, who were distributed by gestation term (up to 34 weeks and after 34 weeks) and the level of sFlt-1:PlGF ratio (<38 is low level, > 110 – high level) was performed. The statistical comparison of the sFlt-1:PlGF ratio with the development of hypertensive disorders during pregnancy and fetal growth retardation (FGR), as well as the duration of the period from research to childbirth was calculated. Results. Preeclampsia (PE) developed in 12 persons out of 40 pregnant women. The sFlt-1:PlGF ratio in the period till 27 weeks of pregnancy in groups of women with PE and without it does not differ with a statistically significant level (p=0.3). In other gestation terms the sFlt-1:PlGF ratio in women with and without placental dysfunction is statistically significant (p<0.05). The sFlt-1:PlGF ratio >38 increases the risk of PE more than 4 times (RR = 4.6) and is statistically significant in a period till 34 weeks [95 % CI: 1.4-14,9]. After 34 weeks of pregnancy the sFlt-1:PlGF ratio >110 has a higher sensitivity (Se=0.75).An analysis of the sFlt-1:PlGF ratio for the purpose of FGR predicting, both in combination with hypertensive disorders during pregnancy or without them, demonstrated its high importance during pregnancy up to 34 weeks (p=0.001). A strong reverse correlation (ƿ= -0.7) was found between the value of the sFlt-1:PlGF ratio and the number of days from the date of research till childbirth at the level of significance of 0.0001 in pregnant women up to 34 weeks. Conclusions. The predictive value of the conventional method of assessing the preeclampsia (PE) risk and the preventive efficiency of acetylsalicylic acid is low. In the absence of clinical manifestation of PE the determination of the sFlt-1:PlGF ratio for a predication till 27 weeks of pregnancy is not informative, so it is not recommended. If the sFlt-1:PlGF ratio is > 38 in the period till 34 weeks, the relative risk is 4.6 [95 % CI: 1.4–14.9]. If the level of the sFlt-1:PlGF ratio is high at first investigation there is no sense to repeat the research in dynamics. In the case of low the sFlt-1:PlGF ratio for a reasonable suspicion of PE development, repeated research can help make an adequate clinical decision. The determination of the sFlt-1:PlGF ratio for a predication or confirmation of fetal growth retardation till 34 weeks is clinically reasonable and informative. There is a strong reverse correlation between the sFlt-1:PlGF ratio and the number of days before the current birth.

SFlt-1 in Chronic Kidney Disease: Friend or Foe?

Placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), are important regulators involved in angiogenesis, atherogenesis, and inflammation. This review article focuses on the function of PlGF/Flt-1 signaling and its regulation by soluble Flt-1 (sFlt-1) in chronic kidney disease (CKD). Elevation of circulating sFlt-1 and downregulation of sFlt-1 in the vascular endothelium by uremic toxins and oxidative stress both exacerbate heart failure and atherosclerosis. Circulating sFlt-1 is inconsistent with sFlt-1 synthesis, because levels of matrix-bound sFlt-1 are much higher than those of circulating sFlt-1, as verified by a heparin loading test, and are drastically reduced in CKD.

SFlt-1/PlGF Ratio Is Not a Good Predictor of Severe COVID-19 nor of Adverse Outcome in Pregnant Women with SARS-CoV-2 Infection-A Case-Control Study.

Elevated serum levels of sFlt-1 were found in non-pregnant severe COVID-19 patients. The aim was to investigate sFlt-1/PlGF ratio as a predictor of severe disease and adverse outcome in pregnant women with COVID-19. A single-center case-control study was conducted in pregnant women with SARS-CoV-2 infection. SARS-CoV-2-negative pregnant women served as controls. Serum sFlt-1/PlGF ratio was assessed. The primary outcome was severe COVID-19 and the secondary outcome comprised adverse outcomes including severe COVID-19, intensive care unit admission, maternal multiple organ failure, preterm delivery, fetal demise, preeclampsia or hypertension diagnosed after COVID-19, maternal death. 138 women with SARS-CoV-2 infection and 140 controls were included. sFlt-1/PlGF ratio was higher in infected patients (11.2 vs. 24; p < 0.01) and in women with severe disease (50.8 vs. 16.2; p < 0.01). However, it was similar in women with adverse and non-adverse outcome (29.8 vs. 20; p = 0.2). The AUC of sFlt-1/PlGF ratio was 0.66 (95% CI 0.56-0.76) for the prediction of severe COVID-19, and 0.72 (95% CI 0.63-0.79) for the prediction of adverse outcome. sFlt-1 and sFlt-1/PlGF ratio are related to SARS-CoV-2 infection and the severity of COVID-19 during pregnancy. However, sFlt-1/PlGF ratio is not a good predictor of severe COVID-19 or adverse outcome.

Angiogenic factors (sFlt-1, PlGF) in twin pregnancy with placentaassociated complications

Aim : to determine reference values of angiogenic factors dynamics in pregnancy for female patients with twins and different types of placentation for early diagnostics and assessment of preeclampsia (PE) severity. Materials and Methods . There was conducted 2020–2021 prospective study enrolling 93 females with twin pregnancy to examine 68 with dichorionic diamniotic (DCDA) twins and 25 with monochorionic diamniotic (MCDA) twins. All patients were divided into 2 groups: group I consisted of 65 women with twin pregnancy without PE, group II included 28 women with twin pregnancy complicated by PE. In blood serum of pregnant women the level of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and their ratio were studied for diagnosing and predicting PE severity at 4 time points of gestation (20.0–23.6 weeks, 24.0–28.6 weeks, 29.0–33.6 weeks, 34.0–36.6 weeks). Results . No significant difference was found in angiogenic factors level and their ratio in pregnant women with uncomplicated DCDA and MCDA twins. Regardless of placentation type, sFlt-1/PlGF ratio in women with twin pregnancy and PE at 24 weeks of gestation was 103.3, by 20-fold exceeding this level than in uncomplicated twin pregnancy. Cut-off values for sFlt-1/PlGF ratio were determined allowing highly reliable to rule out diagnosis PE (sFlt-1/PlGF &lt; 21.85; sensitivity 100 %, specificity 85 %) and to diagnose PE (sFlt-1/PlGF &gt; 49.4; sensitivity 71.1 %, specificity 100 %). The sFlt-1/PlGF ratio was higher in pregnant women with severe PE compared with the moderate degree of the disease throughout pregnancy (р &lt; 0.05). In pregnant women with early PE, the angiogenic factors ratio exceeded the upper threshold value from 24 weeks of gestation, with late PE – from 34.0–36.6 weeks. Significantly higher sFlt-1 level (18359 ± 8656 pg/ml vs. 5526 ± 2808 pg/ml; р &lt; 0.001) and the sFlt-1/PlGF ratio (118,0 ± 65,2 vs. 32,8 ± 18,6; р &lt; 0.03) as well as severe degree of PE were noted in patients with induced twin pregnancy from 24.0–28.6 weeks of gestation compared with spontaneous multiple pregnancy (42,2 and 22,2 % respectively; p &lt; 0,05). Conclusion . The developed reference values of the sFlt-1/PlGF ratio in pregnant women with twins and different types of placentation can be used not only to diagnose PE, but also to assess the severity and timing of the disease manifestation.

EVALUATION OF CERTAIN BIOCHEMICAL AND ANGIOGENIC MARKERS IN THE FIRST TRIMESTER OF PREGNANCY IN WOMEN WITH UMBILICAL CORD PATHOLOGY

At the stage of formation of fetoplacental complex, various factors of the external and internal environment create prerequisites for subsequent unfavorable course of pregnancy and childbirth. Their influence falls on the period of formation and differentiation of extraembryonic structures in the first trimester of pregnancy. That is why umbilical cord pathologies are considered to be one of the main causes of the development of fetal distress, low birth weight and post-hypoxic states of newborns.&#x0D; The purpose of the research: to analyze changes in the parameters of certain biochemical and angiogenic markers in patients with umbilical cord pathology.&#x0D; Research materials and methods. Medical documentation of 56 patients (the main group) with umbilical cord pathology and abnormalities of its insertion (27 pregnant women with a single umbilical artery and 29 women with velamentous insertion) was processed. The comparison group included 30 patients with normal structural components of the umbilical cord. The level of free ȕ-hCG, PAPP-A, free estriol, AFP, placental lactogen, certain growth factors PIGF and sFlt-1 was evaluated using the method of immunoenzymatic analysis. “Astraia Obstetrics” software (“Astraia software gmbH”, Germany) was used to determine the risk of preeclampsia, chromosomal abnormalities, fetal growth retardation, and premature birth.&#x0D; Research results and their discussion. An imbalance in the concentration of PAPP-A and β-hCG, when its low levels corresponded to high levels of β-hCG, was revealed in the main group. An increase in the average values of the level of PAPP-A MoM was established in almost half of the observations (42.9%), a significantly higher level of free ȕ-hCG was noted in 28.6 % of samples. The combined indicators of the concentration of PlGF in women with umbilical cord pathology were significantly lower (by 1.6 times) compared to the data of the comparison group; placental lactogen has a tendency to decrease. The combined values of the concentration of PlGF in women with umbilical cord pathology were significantly lower (by 1.6 times) compared to the data of the comparison group, and the indicators of the level of sFlt-1 – by 1.5 times (p&lt;0.05). This made it necessary to evaluate the calculated parameters of the angiogenic coefficient, which reflects the depth of vascular disorders and the severity of vascular imbalance.. At the same time, this ratio was found to be 2.0 times lower in the patients of the comparison group compared to the combined total indicator in the main group - in pregnant women with umbilical cord pathology - 155.7 units. (p&lt;0.05)&#x0D; Conclusions. Among pregnant women with umbilical cord pathology, a high proportion of the increased PAPP-A indicator, probably a lower level of free β-chorionic gonadotropin subunit, and low parameters of placental lactogen in the third trimester of pregnancy were observed. The combined indicators of the concentration of PlGF in women with umbilical cord pathology were significantly lower (by 1.6 times), and the indicators of sFlt-1 level – by 1.5 times higher compared to the data of the comparison group, which can be a marker of the abnormal formation of fetoplacental complex with the deterioration of the intrauterine fetal condition, as well as an increase in the angiogenic factor. The use of “Astraia Obstetrics” module in combination with prenatal biochemical screening made it possible to assign 23.2 % of examined patients with umbilical cord pathology to the risk group for the development of chromosomal abnormalities, preeclampsia, fetal growth retardation and premature birth.

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms–like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

MiR-2115-3p inhibits ferroptosis by downregulating the expression of glutamic-oxaloacetic transaminase in preeclampsia

IntroductionRecently, ferroptosis has been reported to be closely related to preeclampsia (PE). However, the mechanisms associated with ferroptosis in PE have been poorly studied. MethodsA PE rat model was established via reduced uterine perfusion pressure (RUPP) surgery. A Ferroptosis inhibitor was used to treat the model rats. Blood pressure, urine protein, sFlt-1, GSH, GSH-PX, MDA, total Fe, Fe (II), and Fe (Ⅲ) levels were detected. Placenta morphological changes and fetal survival rate were observed and counted, respectively. miRNA sequencing and bioinformatical analysis were conducted to establish the ferroptosis-related interaction network of miRNAs-mRNAs in PE. After hypoxia treatment, cells were silenced glutamic-oxaloacetic transaminase1 (GOT1) or overexpressed miR-2115-3p/GOT1. Cellular proliferation, invasion, and reactive oxygen species (ROS) were determined. The ferroptosis-related factors levels (ACSL4, TfR1, GPX4, SCL7A11, GSH, GSH-PX, Fe (II), and MDA) were quantified. ResultsIn vivo, ferrostatin-1 attenuated ferroptosis in the PE models, significantly increasing fetal survivability. The miR-2115-3p/GOT1 pathway was screened for possible association with abnormal ferroptosis in PE. miR-2115-3p was discovered to interact with the mRNA of GOT1. Inhibition of GOT1 and overexpression of miR-2115-3p reversed the decrease in cell proliferation capacity, GSH, GSH-PX, and GPX4 levels, and the increase in ROS, ACSL4, TfR1, MDA, total Fe, and Fe (II) levels induced by hypoxia. However, simultaneous overexpression of miR-2115-3p and GOT1 reversed the above results of overexpression of miR-2115-3p. DiscussionmiR-2115-3p might interact with the GOT1 mRNA to downregulate its expression, further inhibiting the hypoxia-promoted ferroptosis in a PE model.

INDICATORS OF ANGIOGENESIS IN PREGNANT WOMEN WITH ARTERIAL HYPERTENSION

The role of the factors of angiogenesis and hormones of pregnancy in pregnant women with hypertension has been studied inadequately and their interaction in such patients is not fully elucidated at present time. Aim. To detect peculiarities of angiogenesis factors and placental hormones in pregnant women with arterial hypertension I and II grades in comparison with results of healthy pregnant women. Materials and methods. Conducting a prospective study of 88 pregnant women, which included: analysis of clinical and anamnestic characteristics and study of the peculiarities of pregnancy in women with chronic hypertension in the first trimester of pregnancy (11-12 weeks). The open prospective controlled study involved 61 pregnant women with chronic arterial hypertension (CAH) 1-2 degree, who were included in the first - the main group. The second control group included 27 healthy pregnant women with physiological pregnancies. Among the angiogenesis indices, the placental growth factor (PlGF), as a pro-angiogenic factor and placental soluble fms-like tyrosine kinase (sFlt-1) was determined as an anti-angiogenic factor, sFlt-1/PlGF ratio was also estimated. Statistical analysis was done by using «STATISTICA® for Windows 6.0» (Stat Soft Inc., № AXXR712D833214FAN5). Results. In the first trimester of pregnancy (11-12 weeks of gestation) in women with CAH is determined by a shift in the balance between pro- and antiangiogenic factors, manifested by statistically significant (p˂0.05) increase in sFlt-1 levels (1700, 9 pg / ml) and a decrease in PlGF levels in3.7 times (9.1 pg / ml) and, accordingly, an increase in the levels of the coefficient K in 5.3 times (sFlt-1 / PlGF) (184.5). The mean values of estradiol, progesterone and chorionic gonadotropin levels in pregnant women with CAH did not differ statistically significantly from those of the control group (p˃0.05). These changes indicate the presence of angiogenesis disorders in pregnant women with chronic hypertension, starting from the first trimester of gestation. Conclusions. Pregnant women with CAH in І trimester have disturbances in balance between pro-angiogenic and anti-angiogenic factors with prevalence of sFlt-1 and reducing of PlGF in serum plasma. Due to such disbalance in pregnant women with CAH of 1 and 2 grade changed cooperation between angiogenesis factors and hormones from direct to inverse. It may lead to development of placental insufficiency in future. That’s why treatment/prophylaxis of it should be administered to pregnant women with CAH in 1 trimester.

Imbalanced Angiogenesis in Pregnancies Complicated by SARS-CoV-2 Infection.

COVID-19 and preeclampsia (preE) share the ANG-II mediated endothelial dysfunction, resulting from a significant dysregulation of RAS and an imbalanced proportion of anti-angiogenic and pro-angiogenic soluble plasmatic factors. Of note, an increased incidence of preE has been reported among COVID-19-infected mothers compared to the general pregnant population. The two most promising angiogenic markers are the soluble fms-like tyrosine kinase receptor-1 (sFlt-1), the major antiangiogenic factor, and the placental growth factor (PlGF), a powerful angiogenic factor. Since these markers have proven useful in the prediction, diagnosis, and severity of preE, this study aimed to evaluate their maternal serum levels in pregnancies complicated by SARS-CoV-2 infection and to assess their potential use to guide the management of these women. A retrospective analysis of SARS-CoV-2-positive pregnant women was performed. The serum levels of sFlt-1 and PlGF were collected at the diagnosis of SARS-CoV-2 infection at the hospital, before the beginning of steroid/hydroxychloroquine and/or antithrombotic therapy. The sFlt-1/PlGF ratio was stratified using cut-off values clinically utilized in the diagnosis and prediction of preE (low < 38, intermediate 38–85/110* and high >85/110*, * if before or after the 34th week of gestation). A total of 57 women were included, of whom 20 (35%) had signs and symptoms of COVID-19 at hospital presentation and 37 (65%) were asymptomatic. None were vaccinated. The mean gestational age at diagnosis of SARS-CoV-2 infection was 32 weeks in symptomatic patients and 37 weeks and 5 days in asymptomatic ones (p = 0.089). sFlt-1 serum levels were higher in SARS-CoV-2 positive asymptomatic patients compared to women with COVID-19 related symptoms (4899 ± 4357 pg/mL vs. 3187 ± 2426 pg/mL, p = 0.005). sFlt-1/PlGF at admission was <38 in 18 of the 20 symptomatic women (90%) compared to 22 (59%) of the asymptomatic patients (p = 0.018). Of note, two of the three women admitted to the intensive care unit had a very low ratio (<2). In turn, rates of patients with sFlt-1/PlGF at admission > 85/110 were not significantly different between the two groups: 11% in asymptomatic patients (4/37) vs. none of the symptomatic patients (p = 0.286), and all of them presented a placental dysfunction, like preE (n = 1) and FGR (n = 3). Of note, there were no stillbirths or maternal or neonatal deaths among symptomatic patients; also, no cases of preE, FGR, or small for gestational age neonates were diagnosed. In conclusion, our data suggest that SARS-CoV-2 infection during pregnancy could influence the angiogenic balance. A significant pathological alteration of the sFlt-1/PlGF ratio cannot be identified during the symptomatic phase; however, if left untreated, SARS-CoV-2 infection could potentially trigger placental dysfunction.

Associations of soluble fms-like tyrosine kinase-1 with cardiovascular events and stroke in patients with atrial fibrillation and suspected or known coronary artery disease: the EXCEED-J study

Abstract Background Atrial fibrillation (AF) increases the risk of stroke. Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction, which are associated with both AF and coronary artery disease (CAD). Recently, we demonstrated that sFlt-1 is independently associated with major adverse cardiovascular (CV) events (MACE) in patients with suspected or known CAD. However, the prognostic utility of sFlt-1 in patients with AF remains unknown. Methods Using data from a multicenter, prospective cohort of 3255 patients with suspected or known CAD, we investigated whether AF modifies the prognostic utility of sFlt-1. Heparin-free serum levels of sFlt-1, N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin-I, high-sensitivity C-reactive protein, cystatin C, neutrophil gelatinase-associated lipocalin, VEGF, and placental growth factor were measured in 324 patients with AF and 2931 patients without AF. The primary outcome was MACE defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, stroke, heart failure (HF) hospitalization, and coronary/peripheral artery revascularization. The biomarkers were natural log-transformed for use as continuous variables. Results After adjustment for potential clinical confounders including anticoagulant drug use, sFlt-1 was significantly associated with MACE (hazard ratio for 1 standard deviation increase [HR], 1.55; 95% confidence interval [CI], 1.14–2.08), CV death (HR, 1.68; 95% CI, 1.10–2.48), and stroke (HR, 1.89; 95% CI, 1.16–3.10), but not with all-cause death (HR, 1.32; 95% CI, 0.99–1.73), HF hospitalization (HR, 0.97; 95% CI, 0.73–1.25), or revascularization (HR, 0.99; 95% CI, 0.74–1.28) in patients with AF, whereas sFlt-1 was significantly associated with MACE (HR, 1.19; 95% CI, 1.02–1.37), all-cause death (HR, 1.19; 95% CI, 1.05–1.34), CV death (HR, 1.26; 95% CI, 1.03–1.48), and HF hospitalization (HR, 1.26; 95% CI, 1.11–1.42), but not with stroke (HR, 1.06; 95% CI, 0.81–1.33) or revascularization (HR, 1.01; 95% CI, 0.95–1.07) in patients without AF. Among other biomarkers, only VEGF was significantly associated with MACE (HR, 1.55; 95% CI, 1.02–2.44), and no biomarkers were significantly associated with CV death or stroke in patients with AF. sFlt-1 added incremental prognostic information for MACE (P=0.005 for net reclassification improvement [NRI], P=0.026 for integrated discrimination improvement [IDI]) and stroke (P=0.034 for NRI, P=0.018 for IDI), but not for CV death (P=0.021 for NRI, P=0.134 for IDI), to the model with potential clinical confounders in patients with AF. Conclusions sFlt-1 independently predicted MACE and stroke in patients with AF and suspected or known CAD. sFlt-1 may serve as a novel prognostic biomarker to stratify the risk of MACE and stroke in patients with AF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Health Labour Sciences Research Grant (2013-2014), AMED (2015-2017, Grant Number JP17ek0210008)

Soluble FMS-Like Tyrosine Kinase-1: Role in placenta accreta spectrum disorder

Background: Placenta accreta is a pregnancy condition where the placenta's blood vessels attach too deeply to the uterine wall. Incidence of placenta accreta is increasingly seen today as the rate of cesarean section increases, however, the exact pathophysiology of this condition is still not fully understood. Soluble fms-like tyrosine kinase-1 (sflt-1) as a protein produced by the placenta was found to be decreased in placenta accreta, Therefore we aim to see if sfltsFlt-1 has a role in the development of placenta accreta. Methods: This study involved 40 samples from patients that had been diagnosed with placenta accreta spectrum disorder (case group), and 40 samples from patients with normal pregnancies (control group) at Rumah Skit Umum Pusat H.Adam Malik (RSUP) Haji Adam Malik Medan, in Indonesia. Diagnosis of placenta accreta syndrome was based on Placenta Accreta Spectrum Score (PAS), and International Federation of Gynecology and Obstetrics (FIGO) classification of placenta accreta spectrum disorder.Analyses were performed by independent t-test, man Mann-Whitney U test, and Kruskal-Wallis analysis test, with a P-value &lt;0.05 considered as statistically significant (95%CI). Results: Based on this study, we found that the sFlt-1 level in the case group was lower than the control group. Data analysis using the Kruskal-Wallis test showed that there was a difference in sFlt-1 levels in this study group (p = 0.02), which was further evaluated with post hoc analysis using Mann. -Whitney U test. The results indicated that there were significant differences between the control and PAS 0, PAS1, and PAS 2 (p = 0.043; p = 0.002; p = 0.03). Conclusion: sFlt-1 levels decreased in placental invasive pregnancies compared to normal pregnancies, however, this still needs to be investigated further in a multi-center study, considering that sFlt-1 levels are also influenced by ethnicity and other conditions that cannot be excluded in this study.

Predictive Value Analysis of Serum sFlt-1 and PLGF Levels/Ratio in Preeclampsia

Background: This study is to explore the clinical significance of serum sFlt-1, and placental growth factor (PLGF) contents, as well as sFlt-1/PLGF ratio in predicting and diagnosing preeclampsia. Methods: Peripheral venous blood was collected from all pregnant women at 11–33+6 weeks for biomarker detection. Totally 105 patients with preeclampsia and 57 patients with severe preeclampsia were included. Serum sFlt-1 and PLGF levels were determined, and sFlt-1/PLGF ratio was calculated. Correlation between sFlt-1, PLGF, sFlt-1/PLGF ratio and serum total cholesterol, triglyceride, lactate dehydrogenase and calcium content levels were analyzed. receiver operating characteristic (ROC) analysis was used to evaluate values of sFlt-1, PLGF and sFlt-1/PLGF ratios in disease diagnosis and prediction. Results: Serum sFlt-1 content and sFlt-1/PLGF ratio in Preeclampsia (PE) patients were significantly higher than control. Serum sFlt-1 content and sFlt-1/PLGF ratio of the severe PE group were significantly higher than the PE group. Serum PLGF contents of the PE and severe PE group were significantly lower than control, and the difference in PLGF content between the severe and PE groups was not significant. There was a moderate correlation between the sFlt-1 content and the lactate dehydrogenase level. There was a low-level correlation between the sFlt-1/PLGF ratio and the lactate dehydrogenase level. The receiver ROC curve analysis showed that sFlt/PLGF had greater predictive value for preeclampsia, with a sensitivity of 98.1% and a specificity of 78.2%. Conclusions: Serum sFlt-1 level and sFlt-1/PlGF ratio have better predictive and diagnostic values, as well as better auxiliary efficiency for preeclampsia. The diagnostic efficiency of sFlt-1/PlGF ratio is better than sFlt-1 content alone.

The effect of genistein on IGF-1, PlGF, sFLT-1 and fetoplacental development

The mechanisms by which genistein, a phytoestrogen, affects fetoplacental development adversely are still poorly understood. It is reported that genistein ingestion modulates thyroid functions, leptin hormone, C-reactive protein, and thyroxin kinase activities. In this study, we evaluated changes in serum and placental insulin-like growth factor-I (IGF-1), placental growth factor (PIGF), and soluble fms-like tyrosine kinase-1 (sFLT-1) in pregnant rats exposed to genistein using ELISA. According to the treatments, Rats were divided into control, 2 mg genistein, and 4 mg genistein groups. Genistein groups were administered with the doses orally from gestational day (GD) one onwards until sacrifice, while the control group received an equal volume of distilled water the vehicle. At GD-12, GD-16, and GD-20, serum samples and placenta homogenates were prepared from maternal blood samples and the placenta and were analysed to determine the concentration of IGF-1, sFLT-1, and PIGF. Serum IGF-1 and PIGF were both increased in all genistein groups at GD-12 and GD-16, and at GD-20 in the 4 mg group. However, serum IGF-1and PIGF levels were decreased in the placenta from all genistein groups at GD-20. Placenta sFLT-1 levels increased at both GD-16 and GD-20 in genistein-treated rat serum. An initial decrease in placental sFLT-1 at GD-12 was followed by an increase at GD-16 and finally a decrease at GD-20 in all genistein-treated rats. The sFL-1/PlGF ratio in placenta samples of genistein-exposed rats was decreased at GD-16 and increased at GD-20, while the reverse was recorded in the serum sample at the same gestational periods. The fetoplacental growth disruption mechanism of genistein can be partly explained by its interference with placental growth factor signalling.

Neuro-oncological Ventral Antigen 2 Regulates Splicing of Vascular Endothelial Growth Factor Receptor 1 and Is Required for Endothelial Function

Pre-eclampsia (PE) affects 2–8% of pregnancies and is responsible for significant morbidity and mortality. The maternal clinical syndrome (defined by hypertension, proteinuria, and organ dysfunction) is the result of endothelial dysfunction. The endothelial response to increased levels of soluble FMS-like Tyrosine Kinase 1 (sFLT1) is thought to play a central role. sFLT1 is released from multiple tissues and binds VEGF with high affinity and antagonizes VEGF. Expression of soluble variants of sFLT1 is a result of alternative splicing; however, the mechanism is incompletely understood. We hypothesize that neuro-oncological ventral antigen 2 (NOVA2) contributes to this. NOVA2 was inhibited in human umbilical vein endothelial cells (HUVECs) and multiple cellular functions were assessed. NOVA2 and FLT1 expression in the placenta of PE, pregnancy-induced hypertension, and normotensive controls was measured by RT-qPCR. Loss of NOVA2 in HUVECs resulted in significantly increased levels of sFLT1, but did not affect expression of membrane-bound FLT1. NOVA2 protein was shown to directly interact with FLT1 mRNA. Loss of NOVA2 was also accompanied by impaired endothelial functions such as sprouting. We were able to restore sprouting capacity by exogenous VEGF. We did not observe statistically significant regulation of NOVA2 or sFLT1 in the placenta. However, we observed a negative correlation between sFLT1 and NOVA2 expression levels. In conclusion, NOVA2 was found to regulate FLT1 splicing in the endothelium. Loss of NOVA2 resulted in impaired endothelial function, at least partially dependent on VEGF. In PE patients, we observed a negative correlation between NOVA2 and sFLT1.

A case report of pre-eclampsia-like endothelial injury in the kidney of an 85-year-old man treated with ibrutinib

BackgroundGlomerular endotheliosis is the pathognomonic glomerular lesion in pre-eclampsia that has also been described in those taking tyrosine kinase inhibitors for cancer treatment. Ibrutinib is a Bruton’s tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia (CLL). We report the first known case of glomerular endotheliosis on kidney biopsy in a patient on ibrutinib monotherapy.Case presentationThe patient presented with acute on chronic kidney disease, proteinuria, low C3 and C4 and a high rheumatoid factor titer. A kidney biopsy was performed to confirm a preliminary diagnosis of membranoproliferative glomerulonephritis (MPGN), the most common glomerular disease in patients with CLL. Unexpectedly, the kidney biopsy showed pre-eclampsia-like lesions on light and electron microscopy: occlusion of glomerular peripheral capillary lumens by swollen reactive endothelial cells. Findings of glomerulonephritis were not seen, and there were no specific glomerular immune deposits by immunofluorescence or electron microscopy.ConclusionsCLL is known to cause glomerular lesions, mainly MPGN. There is increasing evidence that ibrutinib, a major treatment for CLL, can cause kidney disease, but the precise pathology is not characterized. We present a patient with CLL on ibrutinib with signs of glomerular endotheliosis. Based on the absence of CLL-induced kidney pathologies typically seen on the kidney biopsy and the non-selectivity of ibrutinib, we attributed the glomerular endotheliosis to ibrutinib. In pre-eclampsia, increased soluble fms-like tyrosine kinase 1 (sFlt1) levels induce endothelial dysfunction by decreasing vascular endothelial growth factor (VEGF). Ibrutinib has been demonstrated to have non-selective tyrosine kinase inhibition, including inhibition of VEGF receptor (VEGFR) and epidermal growth factor receptor (EGFR). VEGFR and EGFR inhibitors have recently been described in the literature to cause hypertension, proteinuria, and glomerular endotheliosis. Kidney biopsy should be performed in CLL patients on ibrutinib that present with acute kidney injury (AKI) or proteinuria to determine whether the clinical picture is attributable to the disease itself or a complication of the therapy.

Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction.

Preeclampsia and fetal growth restriction (FGR) are both associated with an increased ratio of sFLT1 (soluble fms-like tyrosine kinase-1) to PlGF (placenta growth factor) in maternal serum. In preeclampsia, it is assumed that increased placental release of sFLT1 results in PlGF being bound and inactivated. However, direct evidence for this model is incomplete, and it is unclear whether the same applies in FGR. We conducted a prospective cohort study where we followed 4212 women having first pregnancies from their dating ultrasound, obtained blood samples serially through the pregnancy, and performed systematic sampling of the placenta after delivery. The aim of the present study was to determine the relationship between protein levels of sFLT1 and PlGF in maternal serum measured at ≈36 weeks and placental tissue lysates obtained after term delivery in 82 women with preeclampsia, 50 women with FGR, and 132 controls. The sFLT1:PlGF ratio was increased in both preeclampsia and FGR in both the placenta and maternal serum. However, in preeclampsia, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental sFLT1 level (r=0.45; P<0.0001) but not placental PlGF level (r=-0.17; P=0.16). In contrast, in FGR, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental PlGF level (r=-0.35; P=0.02) but not sFLT1 level (r=0.04; P=0.81). We conclude that the elevated sFLT1:PlGF ratio is primarily driven by increased placental sFLT1 in preeclampsia, whereas in FGR, it is primarily driven by decreased placental PlGF.

Features of vasoactive substance regulation in chorionic villi in women with spontaneous abortion and active cytomegalovirus infection

The aim of the study was to assess the levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), and vascular endothelial growth factor A (VEGF-A) in tissue extracts in comparison with the histologic examination of the endometrium and chorionic villi in women with spontaneous abortion and active cytomegalovirus (CMV) infection.Materials and methods. 81 women at 7–9 weeks of pregnancy were examined: of them, 51 women were CMVseropositive with active infection and after spontaneous abortion, and 30 patients were CMV-seronegative, healthy women after therapeutic abortion. Immunoglobulins (Ig) M and G to CMV and CMV IgG avidity were measured in the blood plasma; sFlt1, PlGF, and VEGF-A were determined in extracts of chorionic villi by enzyme immunoassay. CMV DNA was detected in mononuclear cells of peripheral blood, urine, and chorionic villi by real-time polymerase chain reaction (PCR). A histologic examination of the endometrium and chorionic villi was carried out.Results. In chorionic villus extracts of women with spontaneous abortion and active CMV infection, the concentration of sFlt1 was 3.25 times higher (p &lt; 0.001), and the levels of PlGF and VEGF-A were 1.31 (p &lt; 0.001) and 2.16 times lower (p &lt; 0.001) than in healthy women. A strong negative correlation was established between the levels of sFlt1 and PlGF (r = –0.702; p &lt; 0.001) and VEGF-A (r = –0.858; p &lt; 0.0005), and a positive correlation was revealed between PlGF and VEGF-A levels (r = 0.860; p &lt; 0.001). According to the data of the histologic examination, a lag in decidual transformation of uterine vessels, trophoblast invasion, growth and differentiation of villi, and formation of fetal circulation was detected.Conclusion. The mechanisms of spontaneous abortion in women with active CMV infection include an imbalance of pro- and anti-angiogenic factors, which causes impaired placental development and uteroplacental circulation.

The effect of nicotine-containing products and fetal sex on placenta-associated circulating midpregnancy biomarkers

BackgroundIn utero exposure to nicotine, largely assessed by smoking, is a risk factor for impaired offspring health, while potential effects of non-combustible nicotine use such as snus (oral moist tobacco), are less well-known. Maternal serum concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) may be viewed as “placenta health markers”, known to differ by fetal sex. Maternal smoking during pregnancy has been associated with lower levels of circulating sFlt-1, while the effect of snus on placenta-associated angiogenic factors is unknown. Our aim was to explore if snus and/or smoking exposure was associated with midpregnancy maternal levels of sFlt-1, PlGF and sFlt-1/PlGF ratio if these associations were modified by fetal sex.MethodsMidpregnancy (16–22 gestational weeks) serum from 2603 Scandinavian women enrolled in the population-based multi-center PreventADALL (Preventing Atopic Dermatitis and ALLergies in children) study was analysed for sFlt-1 and PlGF concentrations by electrochemiluminescence, deriving the sFlt-1/PGF ratio. Nicotine use was assessed by electronic questionnaires at enrollment in 2278 of the women. Univariable and multivariable linear regression models on log transformed outcomes were used to assess the association between nicotine use and biomarker levels. Interaction terms were included to identify whether the associations were modified by fetal sex.ResultsMedian sFlt-1, PlGF and sFlt-1/PlGF ratios among women with nicotine exposure information were similar to those of all included women and differed by fetal sex. Current snus use was significantly associated with reduced maternal circulating PlGF levels in adjusted analyses [β − 0.12, (95% CI − 0.20; 0.00) compared to never use, p = 0.020]. A significant interaction between fetal sex and snus exposure was observed for PIGF (p = 0.031). Prior or periconceptional snus use was significantly associated with PIGF in male fetus pregnancies [β − 0.05 (95% CI − 0.09 to (− 0.02)) and β − 0.07 (95% CI − 0.12 to (− 0.02)) compared to never use, p = 0.002]. Smoking was not significantly associated with any circulating biomarkers levels.ConclusionsMidpregnancy maternal angiogenic profile differed by periconceptional snus use and fetal sex. Snus exposure, perceived as “safe” by users, before or during pregnancy seems to affect midpregnancy placental health in a sex dimorphic manner.

Physalis angulata leaf extract ameliorates L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia symptoms in rats through improved endothelial progenitor cells and endothelial cells due to reduced antiangiogenic factor and oxidative stress

Background: This study aimed to determine the ameliorative effects of Physalis angulata leaf extract on L-NG-nitroarginine methyl ester (L-NAME)-induced preeclampsia symptoms in rats. Methods: Phytochemical analysis of the extract was performed with liquid chromatography-high resolution mass spectrometry (LC-HRMS). Pregnant Wistar rats were randomly divided into five groups (n=6). Preeclampsia rats were injected with L-NAME on gestation days 9 to 18 (G9–G18), while sham rats were injected with the same vehicle volume. Three groups of preeclampsia rats were orally supplemented with the extract at doses of 500, 1500, and 2500 mg/kg body weight/day on G12–G18. The tail-cuff method measured blood pressures. Spectrophotometry determined urine protein levels. Serum soluble fms-like tyrosine kinase (sFlt)-1 levels were evaluated using an enzyme-linked immunosorbent assay (ELISA). Serum and placental malondialdehyde (MDA) levels, superoxide dismutase (SOD) activities, and nitric oxide (NO) levels were measured by colorimetry. Immunohistochemistry was used to determine tail artery endothelial nitric oxide synthase (eNOS), placental eNOS, and placental hypoxia-inducible factor (HIF)-1α expressions. Circulating angiogenic cells (CACs) and endothelial colony-forming cells (ECFCs) were counted using flow cytometry. Results: L-NAME injection increased blood pressures, 24-h total urine protein level, serum sFlt-1 level, serum and placental MDA levels, percentages of CACs and ECFCs, and placental HIF-1α expression. It also decreased serum and placental SOD activities, serum NO level, tail artery and placental eNOS expressions compared to the sham group. Physalis angulata leaf extract administration lowered blood pressures, urine protein level, sFlt-1 level, MDA levels, percentages of CACs and ECFCs, and placental HIF-1α expression. The extract increased SOD activities, NO level, tail artery and placental eNOS expressions compared to the preeclampsia group. Conclusions: Physalis angulata leaf extract reduces antiangiogenic factor and oxidative stress. It also enhances eNOS/NO signaling. Thus, it improves EPC and endothelial cell function and reverses L-NAME-induced hypertension and proteinuria in preeclampsia rats.

Does HAART dysregulate angiogenesis in HIV infected preeclampsia?

A dysregulation of angiogenic mediators has been implicated in HIV infection. Inconsistent data exists on highly active antiretroviral therapy (HAART) usage in pregnancy and its association with PE development. In view of the high prevalence of HIV infection and PE in SA, this study was aimed at determining PlGF and sFlt-1 levels in HIV-infected normotensive and preeclamptic pregnancies treated with HAART. Both PlGF and sFlt-1 were quantified in serum from HIV positive [normotensive (N+) and preeclamptic (P+)]; and HIV negative [normotensive (N-) and preeclamptic (P-)] pregnancies, using a Milliplex Multiplex immunoassay. sFlt-1 was significantly upregulated in P+ vs the N+ groups. PlGF was significantly downregulated in PE vs normotensive groups, regardless of HIV status. sFlt-1/PlGF ratio was significantly increased in PE- vs the N- groups. We report an amplification of sFlt-1 in lieu of PlGF down-regulation in HIV-infected pregnancies receiving HAART .