sFlt-1 Levels Research Articles

Relationships of serum placental growth factor and soluble fms-like tyrosine kinase-1 with fetal and uterine artery Doppler indices in pre-eclampsia.

To compare serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) concentrations among women with pre-eclampsia and healthy control women and to evaluate the associations of serum PlGF and sFlt-1 with fetal and uterine artery Doppler indices in pre-eclampsia. A prospective cross-sectional study of 33 women with pre-eclampsia and 33 normotensive pregnant women attending a university hospital in China between January and November 2014. Serum PlGF and sFlt-1 were assayed by enzyme linked immunosorbent assays. Doppler indices of the uterine artery, umbilical artery, fetal middle cerebral artery, and ductus venosus were measured. The pulsatility index of the uterine artery was negatively correlated with PlGF (r, -0.487; P=0.004) and positively correlated with sFlt-1 (r, 0.420; P=0.015). Gestational age at birth was positively correlated with PlGF (r, 0.601, P<0.001) and negatively correlated with sFlt-1 (r, -0.568; P=0.001). Birth weight was positively correlated with PlGF (r, 0.555; P=0.001) and negatively correlated with sFlt-1 (r, -0.552; P=0.001). Apgar score was negatively correlated with sFlt-1 (r, -0.427; P=0.017). Lower PlGF and higher sFlt-1 levels in maternal serum were significantly associated with increased uterine arterial impedance in pre-eclampsia.

Angiogenic factors and the risk of preeclampsia: A systematic review and meta-analysis.

BackgroundThe etiological nature of preeclampsia is heterogeneous. The use of biomarkers indices in early pregnancy helps to have appropriate stratification of pregnancies into high- and low risk for the purpose of choosing timely interventions.ObjectiveThe aim of this systematic review was to determine the pathogenic role of soluble soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in the prediction of preeclampsia in women.Materials and MethodsWe performed a systematic search of the international databases including PubMed, Scopus, and Web of Science until August 2017. The quality of included studies was assessed using the Newcastle-Ottawa Scale. The primary outcome in this review was preeclampsia. The statistical heterogeneity was assessed using the X test and quantified by I. Pooled effects size was obtained by random effects model. Subgroup analyses were also carried out.ResultsTotally, 284 records were identified in the initial search and 15 records were finally included in the meta-analysis. The pooled odds ratios (ORs) for the association between the high level of sFlt-1 and low level of PlGF and subsequent development of preeclampsia among women were 5.20 (95% CI: 1.24–9.16) and 2.53 (95% CI: 1.33–3.75), respectively. The mean difference for sFlt-1 and PlGF in women with preeclampsia compared to controls was 1.15 (95% CI: 0.43–1.86) and –0.94 (95% CI: –1.37–0.52), respectively.Conclusion According to the results from this meta-analysis, increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

Circulating HO-1 levels are not associated with plasma sFLT-1 and GTn HMOX1 polymorphism in preeclampsia

ABSTRACTObjectives: We aimed to assess the plasma HO-1 level and its interrelationship with the plasma sFLT-1 level in preeclamptic and healthy pregnant women with different variants of microsatellite polymorphism (GTn) located in the promoter region of the HMOX-1 gene.Methods: HO-1 and sFLT-1 were measured by ELISA. HMOX1 genotyping was performed using fragment analysis.Results: We found similar and higher levels of plasma HO-1 and sFLT-1, respectively, in preeclampsia. Similar genotypes and alleles frequencies were found in both groups and the absence of modulation of HO-1 levels by genotypes were observed.Conclusion: The plasma HO-1 levels are not increased in preeclampsia women and neither related to sFLT-1 levels and GTn polymorphism.

Angiogenic factor and cytokine analysis among patients with renal cell carcinoma treated with adjuvant VEGFR TKIs.

586 Background: VEGFR TKIs are important therapeutic agents in RCC, but their adjuvant use remains limited. Investigating the effects of these medications on circulating angiogenic factors and cytokines in the adjuvant setting can elucidate whether changes in cytokine levels result from drug-host or drug-tumor interactions, and may reveal biomarkers to guide patient selection for adjuvant treatment. Methods: In the ECOG-ACRIN 2805 (ASSURE) trial, patients with resected RCC were randomized to sunitinib, sorafenib, or placebo. Plasma was collected at start of treatment and 4 or 6 weeks after treatment initiation. All paired samples available by July 2010 were analyzed, corresponding to 413 patients. We analyzed VEGF, PlGF, sFlt1, KDR/sVEGFR-2, Ang2, bFGF, HGF, IFNg, IL8, CXCL9, CXCL10, and CXCL11. Mixed effects models were used to test for changes from baseline. Cox models were used to assess associations between disease-free survival (DFS) and angiogenic factor and cytokine levels. Results: VEGF and PlGF increased after 4 weeks on either treatment (p &lt; 0.0001 for both), and at 6 weeks VEGF and PIGF levels returned to baseline for patients on sunitinib (corresponding to the 2 week break in the sunitinib schedule) but not sorafenib. Levels of sFLT-1 decreased after 4 weeks on suntinib and after 6 weeks on sorafenib (p &lt; 0.0001). sVEGFR2 decreased after both 4 and 6 weeks of treatment on both sunitinib and sorafenib (p &lt; 0.0001). Patients on placebo had no significant changes in circulating angiogenic factor or cytokine levels. CXCL-10 levels increased after 4 weeks on both sunitinib and sorafenib but not on placebo, and remained elevated at 6 weeks on sunitinib. Higher baseline CXCL-10 was associated with worse DFS (HR 1.41 per log increase in CXCL-10, Holm adjusted p-value 0.003, 95% CI 1.18-1.70). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG PS. Conclusions: Among patients treated with VEGFR TKIs in the adjuvant setting for RCC, drug-host interactions mediate changes in cytokines and angiogenic factors. Elevated CXCL-10 prior to treatment was associated with higher recurrence risk. Studies to understand the functional consequences of these changes are underway.

Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.

Molecular links between angiogenesis and inflammation in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a cause of infertility in women of reproductive age. Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. The aim is to study roles of parameters associated with angiogenesis and inflammation e.g vascular endothelial growth factor (VEGF), soluble-Fms-like tyrosine kinase (sFlt-1), monocyte chemotactic protein-1 (MCP-1), endostatin and interleukin–18 (IL-18) in PCOS pathogenesis and enlighten possible correlations within PCOS-angiogenesis-inflammation triangle.A total of 64 women, 31 healthy and 33 with PCOS participated into the study. Their ages, body mass index (BMI) values, routine biochemical parameters were recorded. VEGF, MCP-1, sFlt-1, IL-18 and endostatin levels were determined by ELISA in serum samples. Statistical analyses were performed by SPSS. p&lt;0.05 was accepted as the degree for statistical significance.Ages, BMI values and BMI distribution profiles of groups did not differ significantly from each other. There were no significant differences between the values detected for MCP-1, IL-18, VEGF and sFlt-1. Upon evaluation of endostatin values, those of patient group were significantly higher than those in control group (p&lt;0.01). Two important correlations were detected (VEGF and MCP-1 as well as VEGF and sFlt-1) in patient group. These were not observed in the control group.As a result of the literature survey, any study reporting elevated endostatin levels as well as significant correlations between VEGF-MCP-1 and VEGF-sFlt-1 was not found on women with PCOS. In this study, it was concluded that the strikingly elevated values of endostatin in PCOS was a prominent finding.

DIFFERENTIAL DIAGNOSTICS OF PREECLAMPSIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE

THE AIM: To assess the significance of prognostic markers of preeclampsia – sFlt-1 and PlGF in the differential diagnosis of preeclampsia and chronic kidney disease.PATIENTS AND METHODS:patients whom signed informed consent, was taken samples of blood in the third trimester of pregnancy. The study group included 36 patients with preeclampsia, the comparison group of 46 pregnant women with CKD and the control group included 40 healthy patients, with pregnancy without complication.RESULTS: Significant differences in the levels of serum sFlt-1 and PlGF were found: between the PE and the comparison group (CKD), as well as between the PE and the control group (CG), whereas no differences were found between the CG and CKD. The sFlt-1 level was significantly increased in PE compared with CKD and KG (5.12-fold and 4.25-fold higher, respectively). Serum PlGF levels were significantly reduced in PE relative to both CKD and KG (17.4 and 12.5 times lower, respectively). The sFlt-1/PlGF ratio was significantly increased in PE compared with CKD and the control group (approximately 25 times higher in both groups), but there was no significant difference between CKD and CG.CONCLUSION:Thus, the definition of the relationship sFlt-1, PlGF, sFlt-1/PlGF can be used in the differential diagnosis of preeclampsia and chronic kidney disease.

Vascular Cardio-Oncology: Vascular Endothelial Growth Factor inhibitors and hypertension.

Since the formation of new blood vessels is essential for tumour growth and metastatic spread, inhibition of angiogenesis by targeting the vascular endothelial growth factor (VEGF) pathway is an effective strategy for various types of cancer, most importantly renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. However, VEGF inhibitors have serious side effects, most importantly hypertension and nephropathy. In case of fulminant hypertension, this may only be handled by lowering the dosage since the blood pressure rise is proportional to the amount of VEGF inhibition. These effects pathophysiologically and clinically resemble the most severe complication of pregnancy, preeclampsia, in which case an insufficient placenta leads to a rise in sFlt-1 levels causing a decrease in VEGF availability. Due to this overlap, studies in preeclampsia may provide important information for VEGF inhibitor-induced toxicity and vice versa. In both VEGF inhibitor-induced toxicity and preeclampsia, endothelin (ET)-1 appears to be a pivotal player. In this review, after briefly summarizing the anticancer effects, we discuss the mechanisms that potentially underlie the unwanted effects of VEGF inhibitors, focusing on ET-1, nitric oxide and oxidative stress, the renin-angiotensin-aldosterone system, and rarefaction. Given the salt sensitivity of this phenomenon, as well as the beneficial effects of aspirin in preeclampsia and cancer, we next provide novel treatment options for VEGF inhibitor-induced toxicity, including salt restriction, ET receptor blockade, and cyclo-oxygenase inhibition, in addition to classical antihypertensive and renoprotective drugs. We conclude with the recommendation of therapeutic drug monitoring to improve patient outcome.

VEGF and sFLT-1 in serum of PIH patients and effects on the foetus.

The expression of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFLT-1) in the serum of patients with pregnancy induced hypertension (PIH) syndrome and its effects on the foetus was explored. A total of 105 cases of PIH pregnant women admitted to The First People's Hospital of Changzhou from March 2015 to February 2018 were divided into 3 groups according to the severity of the patients condition. Group A (n=35) was hypertension complicating pregnancy, group B (n=46) was mild preeclampsia and group C (n=24) was severe preeclampsia. In addition, 35 healthy pregnant women were selected as the control group. VEGF and sFLT-1 levels in serum were detected by enzyme linked immunosorbent assay, and the correlations between levels of VEGF and sFLT-1, neonatal weight and Apgar score were analyzed. Compared with group A, the level of serum VEGF was lower, while the level of sFLT-1 was higher in groups B and C (P<0.05). Compared with group B, the serum VEGF level in group C decreased significantly (P<0.05), while the serum level of sFLT-1 increased significantly (P<0.05). Compared with group A, neonatal weight and Apgar score in group C was significantly lower (P<0.05). There was a positive correlation between the serum VEGF level and neonatal weight and Apgar score (r=0.435, P<0.001. r=0.357, P<0.001). There was a negative correlation between the serum sFLT-1 level and neonatal weight and Apgar score (r=−0.351, P<0.001. r=−0.422, P<0.001). Therefore, we concluded that VEGF and sFlt-1 may be involved in the occurrence and development of PIH. The decrease of serum VEGF level and the increase of sFlt-1 level may be related to the inhibited fetal growth and development, which is of great significance in the clinical detection of PIH patients.

Association of vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 polymorphisms with their circulating protein levels in preeclampsia

Introduction: Normal development of placental vascular tree requiring angiogenesis and vasculogenesis is structurally and functionally indispensable for both adequate placental growth and delivery of nutrients from mother to the fetus. Impaired placental angiogenesis has been implicated in the pathophysiology of pregnancy complications which have immediate and long-lasting effects on the mother and her child, such as preeclampsia (PE) and fetal growth restriction. The mechanisms underlying the deregulation of placental angiogenesis in PE include a misbalance between the secretion and activity of pro-angiogenic (vascular endothelial growth factor [VEGF]) and anti-angiogenic (soluble fms-like tyrosine kinase-1 [sFlt-1]) factors. Considering the important roles of VEGF and sflt1 in pregnancy, functional polymorphisms in these genes may be potentially important as genetic markers for susceptibility to PE. Thus, the aim of the study was to screen for the presence of VEGF and sFlt-1 gene polymorphisms and to measure their levels in PE patients and controls of Indian origin. Material and Methods: Fifty each of clinically diagnosed patients and gestational and maternal age-matched normotensive, nonproteinuric controls were recruited after taking informed consent. DNA isolated from blood samples was processed for polymerase chain reaction amplification followed by restriction fragment length polymorphism to screen for the presence of VEGF + 936C/T, sFlt-1 (+4244G/A, −4771G/T, −523C/G) polymorphisms. Serum levels of VEGF-A and sFlt-1 were measured by Sandwich enzyme-linked immunosorbent assay (ELISA). Results: Decreased frequency of wild type genotype with respect to VEGF + 936C/T and sFlt-1 (+4244G/A, −4771G/T, and −523C/G) polymorphisms was seen in patients. ELISA results showed lower VEGF-A (198.43 ± 14.63 pg/ml vs. 235.08 ± 16.72 pg/ml [mean ± standard error of mean]) and higher sFlt-1 levels (2932.81 [1802.33–5760.46] pg/ml vs. 1114.94 [655.03–2694.35] Median [Range]; P

Altered expression of vascular endothelial growth factor, vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, and Soluble Fms-like Tyrosine Kinase-1 in peripheral blood mononuclear cells from normal and preeclamptic pregnancies.

Preeclampsia (PE) is the leading cause of maternal and fetal morbidity and mortality. It complicates around 2%-10% pregnancies worldwide due to imbalance between proangiogenic and anti-angiogenic factors, leading to incomplete placentation, ischemia, and endothelial dysfunction. The study was aimed to analyze the mRNA expression of vascular endothelial growth factor (VEGF) and its receptors, i.e., VEGF receptor-1 (VEGFR-1), VEGF receptor-2 (VEGFR-2), and soluble Fms-like tyrosine kinase-1 (sFlt-1) from maternal peripheral blood mononuclear cells (PBMCs) of PE patients. This was a cross-sectional comparative study comprising 18 normotensive and 18 PE patients; the patients were further divided as early-onset preeclampsia (EOP) and late-onset preeclampsia (LOP). The expression level of VEGF, its receptors (VEGFR-1 and VEGFR-2), and sFlt-1 was investigated using real-time polymerase chain reaction. There was a significant change in the mRNA expression with a decrease in VEGF, VEGFR-1, and VEGFR-2 and an increase in sFlt-1 in PBMCs of PE and normal pregnancies (P < 0.001). sFlt-1 mRNA expression was increased by 2.95-fold in the PE group with an inverse correlation with expression of VEGFR-2 (Spearman's rho = 0.68). Based on these findings, we conclude that PE is associated with decrease in the mRNA expression of VEGF, VEGFR-1, and VEGFR-2 as compared to an increase in sFlt-1 in PBMCs.

Follicular Fluid Levels of Adrenomedullin 2, Vascular Endothelial Growth Factor and its Soluble Receptors Are Associated with Ovarian Response During ART Cycles.

Introduction Adrenomedullin 2 (ADM2) and vascular endothelial growth factor (VEGF) affect ovarian function, especially angiogenesis and follicular development. The actions of VEGF can be antagonized by its soluble receptors, soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble VEGF receptor 2 (sVEGFR-2), as they decrease its free form. In the present study, we evaluated the relationship between follicular fluid (FF) levels of AMD2, VEGF and its soluble receptors, and ICSI outcomes. Materials and Methods ICSI cycle outcomes were evaluated and FF levels of VEGF, sFlt-1, sVEGFR-2 and ADM2 were determined using ELISA kits. Results FF levels of ADM2, VEGF, and sVEGFR-2 were significantly higher in non-responders compared to other ovarian response groups (p < 0.05). There were significant correlations between ADM2, VEGF and sVEGFR-2 levels as well as VEGF/sFlt-1 and VEGF/sVEGFR-2 ratios (r = 0.586, 0.482, 0.260, and − 0.366, respectively). Based on the ROC curve, the cutoff value for ADM2 as a non-responder predictor was 348.55 (pg/ml) with a sensitivity of 67.7% and a specificity of 94.6%. Conclusions For the first time we measured FF ADM2 levels to determine the relationship to VEGF and its soluble receptors. We suggest that ADM2 could be a potential predictive marker for non-responders. Although the exact function of ADM2 in ovarian angiogenesis is not yet understood, our study may shed light on the possible role of ADM2 in folliculogenesis and ovulation.

Corrigendum to "Increased serum levels of sFlt-1/PlGF ratio in preeclamptic women with onset at

Corrigendum to "Increased serum levels of sFlt-1/PlGF ratio in preeclamptic women with onset at <32 weeks compared with ≥32 weeks" [Pregnancy Hypertens. 12 (2018) 96-103

Limbal niche cells: a novel feeder cell for autologous cultivated oral mucosal epithelial transplantation.

To establish a culture system using conspecific limbal niche cells (LNCs) as feeders for autologous cultivated oral mucosal epithelial transplantation (COMET). Rabbit oral epithelial sheets, harvested from culture systems containing LNCs or 3T3 cells, were transplanted onto limbal stem cell-deficient rabbit eyes (COMET-3T3 or COMET-LNCs). After COMET, corneas were relatively restored, with the exception of mild neovascularization in one cornea of the COMET-3T3 group. CD34 was detected in COMET-3T3 group corneas. Corneas of the COMET-LNCs group expressed high levels of PEDF and sFlt-1, but low levels of bFGF, compared with expression in COMET-3T3 corneas. The culture system containing conspecific LNC feeders could substitute for the 3T3 cell system and decrease the risk of neovascularization after COMET.

Possibilities for prediction and prevention of preeclampsia in women with diabetes mellitus

Based on the analysis of literature data, the role and serum levels of the main angiogenic (placental growth factor (PlGF)) and antiangiogenic vascular factors (endoglin (sENG), soluble fms-like type 1 tyrosine kinase (sFlt-1)) have been assessed in pregnant women with different types of diabetes mellitus (DM) in both the plasma and placenta. We evaluated the effectiveness of administration of low doses of acetylsalicylic acid for preventing preeclampsia in diabetic pregnancy. In addition, the effectiveness of using the sFlt-1/PlGF and PlGF/sENG ratios as possible test systems for prediction of the complication in this patient population was evaluated. It has been found that the synthesis of the studied biomarkers fails in the diabetic pregnancy, with the expression levels of sENG and sFlt-1 increased and PlGF reduced. However, the insufficient research does not allow us to make unambiguous conclusions about the practical validity of the evaluation of the plasma content of these vascular factors and their ratios for the preeclampsia prediction in pregnant women with DM. The presented data on acetylsalicylic acid administration to these women are also controversial. Given the high incidence of adverse perinatal outcomes associated with DM during pregnancy, an additional assessment of the prognostic risk model for the development of preeclampsia and the appropriateness of aspirin administration is needed. Therefore, further randomized studies are required to address this issue.

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

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. Key words: sFlt-1; PICCO; Extravascular lung water index; Septic shock; Prognosis

Yolk sac-embryo distance in correlation with soluble form of vascular endothelial growth factor levels in pregnancy with potentially reserved evolutivity.

Embryonic demise is a frequent complication of the first trimester pregnancy. The purpose of this study was toevaluate the correlation between a serum biomarker, the soluble form of the vasculo-endothelial growth factor (sFlt-1) andthe distance between the yolk sac (YS) and embryo (DYSE), determined by ultrasonography. Thestudy was a prospective case-control study that included 2 groups of patients - the control group with 81 first-trimester pregnanciesin evolution and the case group with 89 first-trimester pregnancies with a potentially reserved evolutivity. Acorrelation between the serum level of sFlt-1 and DYSE in embryos with crown-rump length (CRL) greater than 5 mm wasidentified, showing that a DYSE ≤3 mm correlates with a low level of sFlt-1 (p<0.05) and a DYSE> 4 mm correlates withan increased level of sFlt-1 (p<0.05). A low level of sFlt-1 associated with a distance between the embryo andyolk sac of small dimensions, respectively <3 mm, correlates with an increased rate of non-viable embryos. This correlationbetween an ultrasound and a serum parameter is of great value and brings important information about the viability of firsttrimester pregnancies.

Clinical Implications

Clinical Implications

Exosomes From Women With Preeclampsia Induced Vascular Dysfunction by Delivering sFlt (Soluble Fms-Like Tyrosine Kinase)-1 and sEng (Soluble Endoglin) to Endothelial Cells.

Preeclampsia is a unique multiple system disorder that affects 5% to 8% of pregnancies. Exosomes, membrane-encapsulated vesicles that are released into the extracellular environment by many cell types, can carry signals to the recipient cells to affect inflammation, apoptosis, and angiogenesis. We hypothesize that exosomes from women with preeclampsia complications impair vascular development by delivering antiangiogenic factors to endothelial cells. In the current study, plasma samples from gestational age-matched preeclampsia and normal pregnancies were used to isolate circulating exosomes by commercial kits. Next, application of transwell and matrigel tube formation assays showed that exosomes from preeclampsia patients impaired angiogenesis of human umbilical vein endothelial cells. We found that exosomes from preeclampsia expressed abundant sFlt-1 (soluble fms-like tyrosine kinase-1) and sEng (soluble endoglin). Considering the possibility that extracellular sFlt and sEng were horizontally transferred to human umbilical vein endothelial cells, we successfully collected exosomes containing high levels of sFlt-1 and sEng by overexpressing them in human embryonic kidney 293 cells. Furthermore, we demonstrated that these exosomes can attenuate the proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro. In a mouse model, exosomes from preeclampsia patients caused vascular dysfunction directly resulted in adverse preeclampsia-like birth outcomes. Thus, we proposed that exosomes mediated efficient transfer of sFlt-1 and sEng to endothelial cells to damage vascular functions and induce complications in preeclampsia patients.

Diagnostic Accuracy of Different Soluble fms-Like Tyrosine Kinase 1 and Placental Growth Factor Cut-Off Values in the Assessment of Preterm and Term Preeclampsia: A Gestational Age Matched Case-Control Study.

Introduction: The objective was to investigate the diagnostic accuracy of different thresholds of the soluble vascular endothelial growth factor receptor-1 (sFlt-1) and the placental growth factor (PlGF) in preterm (≤37 weeks) and term (>37 weeks) preeclampsia (PE).Materials and Methods: A nested case-control study was performed from a high-risk Swiss cohort. Only blood samples on the day of PE diagnosis were included. The primary outcome was to verify the diagnosis using the recently proposed cut-off values for PE (sFlt-1:PlGF ratio of ≥85 in ≤ 34 weeks or ≥110 in >34 weeks), and the gestational age dependent centiles.Results: Thirty-four women with preterm PE were matched with 64 controls and 25 women with term PE with 45 controls. The test performance of the sFlt-1:PlGF ratio in preterm PE was very good (AUROCC of 0.95). The sFlt-1:PlGF ratio could adequately predict adverse fetal or neonatal outcome. In term PE, sFlt-1 alone showed a slightly better diagnostic accuracy with an AUROCC of 0.84. Almost all women with a sFlt-1:PlGF ratio above threshold delivered during the following week.Discussion: In pregnant women with high risk of developing PE, the sFlt-1:PlGF ratio and sFlt-1 levels help clinicians to confirm the diagnosis of imminent preterm PE and can additionally be used to rule out PE at term.