Plasma Levels Of sEng Research Articles

Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis.

Labetalol is used for the therapy of hypertension in preeclampsia. Preeclampsia is characterized by high soluble endoglin (sEng) concentration in plasma and coincides with intrahepatic cholestasis during pregnancy (ICP), which threatens the fetus with the toxicity of cumulating bile acids (BA). Therefore, we hypothesized that both labetalol and increased sEng levels worsen BA cumulation in estrogen-induced cholestasis. C57BL/6J, transgenic mice overexpressing human sEng, and their wild-type littermates were administrated with ethinylestradiol (EE, 10mg/kg s.c., the mice model of ICP) and labetalol (10mg/kg s.c.) for 5days with sample collection and analysis. Plasma was also taken from healthy pregnant women and patients with ICP. Administration of labetalol to mice with EE cholestasis aggravated the increase in BA plasma concentrations by induction of hepatic Mrp4 efflux transporter. Labetalol potentiated the increment of sEng plasma levels induced by estrogen. Increased plasma levels of sEng were also observed in patients with ICP. Moreover, increased plasma levels of human sEng in transgenic mice aggravated estrogen-induced cholestasis in labetalol-treated mice and increased BA concentration in plasma via enhanced reabsorption of BAs in the ileum due to the upregulation of the Asbt transporter. In conclusion, we demonstrated that labetalol increases plasma concentrations of BAs in estrogen-induced cholestasis, and sEng aggravates this retention. Importantly, increased sEng levels in experimental and clinical forms of ICPs might present a novel mechanism explaining the coincidence of ICP with preeclampsia. Our data encourage BA monitoring in the plasma of pregnant women with preeclampsia and labetalol therapy.

Pregnancy-Induced High Plasma Levels of Soluble Endoglin in Mice Lead to Preeclampsia Symptoms and Placental Abnormalities

Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical manifestations of the disease. An increased level of soluble endoglin (sEng) in plasma has been proposed to be an early diagnostic and prognostic biomarker of this disease. A pathogenic function of sEng involving hypertension has also been reported in several animal models with high levels of plasma sEng not directly dependent on pregnancy. The aim of this work was to study the functional effect of high plasma levels of sEng in the pathophysiology of preeclampsia in a model of pregnant mice, in which the levels of sEng in the maternal blood during pregnancy replicate the conditions of human preeclampsia. Our results show that wild type pregnant mice carrying human sEng-expressing transgenic fetuses (fWT(hsEng+)) present high plasma levels of sEng with a timing profile similar to that of human preeclampsia. High plasma levels of human sEng (hsEng) are associated with hypertension, proteinuria, fetal growth restriction, and the release of soluble factors to maternal plasma. In addition, fWT(hsEng+) mice also present placental alterations comparable to those caused by the poor remodeling of the spiral arteries characteristic of preeclampsia. In vitro and ex vivo experiments, performed in a human trophoblast cell line and human placental explants, show that sEng interferes with trophoblast invasion and the associated pseudovasculogenesis, a process by which cytotrophoblasts switch from an epithelial to an endothelial phenotype, both events being related to remodeling of the spiral arteries. Our findings provide a novel and useful animal model for future research in preeclampsia and reveal a much more relevant role of sEng in preeclampsia than initially proposed.

High Soluble Endoglin Levels Affect Bile Acids And Cholesterol Metabolism In Mice Liver

Background and Aims: Increased plasma levels of sEng are observed in patients with cardiovascular and metabolic diseases including hypercholesterolemia, atherosclerosis, and type II diabetes mellitus, which affect liver functions and metabolism. Therefore, we hypothesized that high levels of sEng will affect cholesterol and bile acids (BA) turnover in liver.

High soluble endoglin levels do not induce changes in structural parameters of mouse heart.

A soluble form of endoglin (sEng) released into the circulation was suggested to be a direct inducer of endothelial dysfunction, inflammation and contributed to the development of hypertension by interfering with TGF-β signaling in cardiovascular pathologies. In the present study, we assessed the hypothesis that high sEng level-induced hypertension via a possible sEng interference with TGF-β signaling pathways may result in inflammatory, structural or fibrotic changes in hearts of Sol-Eng+ mice (mice with high levels of soluble endoglin) fed either chow or high-fat diet. Female Sol-Eng+ mice and their age matched littermates with low plasma levels of sEng were fed either chow or high-fat diet (HFD). Heart samples were subsequently analyzed by histology, qRT-PCR and Western blot analysis. In this study, no differences in myocardial morphology/hypertrophy and possible fibrotic changes between Sol-Eng+ mice and control mice were detected on both chow and HFD. The presence of sEng did not significantly affect the expression of selected members of TGF-β signaling (membrane endoglin, TGFβRII, ALK-5, ALK-1, Id-1, PAI-1 and activated Smad proteins-pSmad 1,5 and pSmad 2,3), inflammation, heart remodeling (PDGFb, Col1A1) and endothelial dysfunction (VCAM-1, ICAM-1) in the hearts of Sol-Eng+ mice compared to control mice on both chow and high-fat diet. High levels of soluble endoglin did not affect microscopic structure (profibrotic and degenerative cardiomyocyte changes), and specific parts of TGF-β signaling, endothelial function and inflammation in the heart of Sol-Eng+ mice fed both chow diet or HFD. However, we cannot rule out a possibility that a long-term chronic exposure (9months and more) to soluble endoglin alone or combined with other cardiovascular risk factors may contribute to alterations of heart function and structure in Sol-Eng+ mice, which is the topic in our lab in ongoing experiments.

Maternal and Cord Blood Plasma sEng and TGF-β1 in Patients with Hypertensive Disorders of Pregnancy: A Pilot Study in a South Indian Population.

Hypertensive Disorders of Pregnancy (HDP) are one of the most widespread complications of pregnancy that affects both mother and foetus. It has been observed that in Preeclampsia, the release of soluble angiogenic factors from the ischemic placenta into maternal plasma plays a crucial role in the pathogenesis. To assess the plasma Soluble Endoglin (sEng) and Transforming Growth Factor (TGF-β1) levels in various types of HDP and to correlate the levels of these markers with the pregnancy outcome. A total of 128 pregnant women were recruited and the study was carried out for a period of three years. Cord blood and maternal blood plasma levels of sEng and TGF-β1 were analysed by ELISA kits in Control Pregnant Women (CPW), Gestational Hypertension (GH), Early Onset Preeclampsia (EOPE), Late Onset Preeclampsia (LOPE), and Eclampsia (E) during third trimester. The Gestational Age (GA) at the time of delivery and Birth Weight (BW) of the baby also were also evaluated. The circulating levels of maternal and cord blood sEng were significantly higher in EOPE and E compared to CPW and GH. However, the maternal and cord blood levels of TGF-β1 were significantly lower in LOPE and E when compared to CPW and GH. The GA and BW of the baby were found to be significantly lower in EOPE and E compared to CPW, GH and LOPE. Also, a negative correlation was observed between sEng levels with pregnancy outcome; GA and BW. And also, a positive correlation was found between TGF-β1 and pregnancy outcome. A generalised angiogenic imbalance and poor birth outcomes were observed in HDP. There is a spectrum of biochemical derangements related to angiogenesis in GH, EOPE, LOPE and E.

OS 05-07 ROLE OF SOLUBLE ENDOGLIN IN THE PHYSIOPATHOLOGY OF PREECLAMPSIA

Objective: Preeclampsia, characterized by hypertension and proteinuria occurring after the twentieth week of pregnancy, is a major contributor to maternal and perinatal morbidity and mortality in developed countries. The mechanisms mediating the pathogenesis preeclampsia are far from clear. Strong experimental evidence suggests that placental ischemia, resulting from the inappropriate remodeling of the maternal spiral arteries, stimulates the release of soluble factors causing hypertension and renal damage. Plasma levels of soluble endoglin (sEng) are increased before the clinical onset of preeclampsia, and we have shown that rodents exposed to high circulating levels of sEng show severe preeclampsia-like symptoms (Valbuena-Diez et al, Circulation 2012,126:2612). The purpose of this study is to evaluate if sEng plays some role in the development of preeclampsia. Design and Method: Transgenic mice overexpressing human sEng (sEng + ) were generated. Wild-type (WT) female mice were crossed with sEng + (sEng pregnant) or with WT male (WT pregnant). We measured plasma levels of sEng (ELISA), arterial pressure (tail cuff and telemetry), proteinuria, fetal mass, the histological structure of the placentas at 18th day of pregnancy, and the effect of sEng in the proliferating (MTT) and invading (transwell) ability of trophoblasts in culture. Results: Plasma levels of sEng increased in plasma of sEng pregnant from the 11th day of pregnancy, with a peak on day 13. Systolic pressure was higher in sEng than in WT pregnant mice from the 13th day of gestation and remained increased until delivery. Proteinuria was higher in sEng than in WT pregnant mice. Total fetal weight was lower in sEng than in WT pregnant mice. Placentas from sEng pregnant females showed marked vacuolization and necrosis areas. Incubation with sEng reduced the proliferation, migration and invasiveness of cultured human trophoblasts. Conclusions: Soluble endoglin plays a major role in preeclampsia shown by WT female carrying sEng + fetuses.

Clinical significance of soluble-endoglin levels in systemic lupus erythematosus: possible association with anti-phospholipid syndrome

The pathogenic role of soluble endoglin (s-Eng), as an antiangiogenic protein, has largely been demonstrated in various vascular disorders. Our aim was to assess, in a cross-sectional study, plasma levels of s-Eng in systemic lupus erythematosus (SLE) patients and its relation with the disease characteristics. Plasma from 86 patients with SLE and 36 normal healthy subjects was assayed for s-Eng levels by enzyme-linked immunosorbent assay. Demographic, clinical, autoantibodies and serological data were prospectively assessed. Disease activity was assessed by total SLE disease activity index score. In our SLE patients, the levels of s-Eng were comparable between SLE patients and the control group. However, these levels were significantly associated with antiphospholipid syndrome (APS). In addition, s-Eng levels were significantly associated with antiphospholipid antibodies in our studied population. On the other hand, we did not find significant differences in mean plasma s-Eng levels in relation to disease activity, other organ system involvement or the presence of anti-dsDNA. Our preliminary data indicated the importance of s-Eng in a special subgroup of SLE patients associated with secondary APS. An additional prospective, large-scale, longitudinal study should be carried out to support these findings.

Circulating Soluble Endoglin Levels in Pregnant Women in Cameroon and Malawi—Associations with Placental Malaria and Fetal Growth Restriction

Placental infections with Plasmodium falciparum are associated with fetal growth restriction resulting in low birth weight (LBW). The mechanisms that mediate these effects have yet to be completely described; however, they are likely to involve inflammatory processes and dysregulation of angiogenesis. Soluble endoglin (sEng), a soluble receptor of transforming growth factor (TGF)-β previously associated with preeclampsia in pregnant women and with severe malaria in children, regulates the immune system and influences angiogenesis. We hypothesized that sEng may play a role in development of LBW associated with placental malaria (PM). Plasma levels of sEng were measured in women (i) followed prospectively throughout pregnancy in Cameroon (n = 52), and (ii) in a case-control study at delivery in Malawi (n = 479). The relationships between sEng levels and gravidity, peripheral and placental parasitemia, gestational age, and adverse outcomes of PM including maternal anemia and LBW were determined. In the longitudinal cohort from Cameroon, 28 of 52 women (54%) experienced at least one malaria infection during pregnancy. In Malawi we enrolled two aparasitemic gravidity-matched controls for every case with PM. sEng levels varied over the course of gestation and were significantly higher in early and late gestation as compared to delivery (P<0.006 and P<0.0001, respectively). Circulating sEng levels were higher in primigravidae than multigravidae from both Cameroon and Malawi, irrespective of malarial infection status (p<0.046 and p<0.001, respectively). Peripheral parasitemia in Cameroonian women and PM in Malawian women were each associated with elevated sEng levels following correction for gestational age and gravidity (p = 0.006 and p = 0.033, respectively). Increased sEng was also associated with the delivery of LBW infants in primigravid Malawian women (p = 0.017); the association was with fetal growth restriction (p = 0.003) but not pre-term delivery (p = 0.286). Increased circulating maternal sEng levels are associated with P. falciparum infection in pregnancy and with fetal growth restriction in primigravidae with PM.

Soluble endoglin and transforming growth factor‐β1 in women who subsequently developed preeclampsia

This study aimed to analyze the differences of soluble endoglin (sEng) and transforming growth factor-beta1 (TGF-beta1) according to preeclamptic complications and to investigate the correlation between these factors and the clinical symptoms of preeclampsia. We estimated the levels of sEng and TGF-beta1 in plasma collected in the second trimester at the time of genetic amniocentesis from 60 women who subsequently developed preeclampsia and 124 contemporaneous normotensive women. sEng levels were higher in cases than in controls, whereas TGF-beta1 levels were lower (P < 0.001). sEng levels, but not TGF-beta1 levels, were higher in cases with severe or preterm delivery than in cases with mild preeclampsia or term delivery (P < 0.001) and were increased in cases destined to deliver a small gestational age neonate (P < 0.001). Moreover, sEng levels, but not TGF-beta1 levels, showed a positive correlation with maximum diastolic and systolic blood pressure (r = 0.57, P < 0.001; and r = 0.33, P < 0.001, respectively) and proteinuria (r = 0.42, P < 0.001). Early midtrimester plasma levels of sEng are predictive of subsequence occurrence and severity of preeclampsia, in terms of severity of hypertension and proteinuria, prematurity, and association with small for gestational age neonates.