Endoglin Levels Research Articles

Serum endothelin-1 and NT-proBNP, but not ADMA, endoglin and TIMP-1 levels, reflect impaired right ventricular function in patients with systemic sclerosis

BackgroundHeart and pulmonary involvement is a leading cause of systemic sclerosis (SSc)-related deaths.ObjectivesThe aim of our study was to assess if biochemical markers of right ventricular (RV) overload, endothelial function and collagen metabolism can predict RV dysfunction assessed by Doppler echocardiography in SSc patients.MethodsWe prospectively studied 111 consecutive patients (101 F, 10 M, age 54.2 ± 13.8 years) with diagnosed SSc (mean disease duration 9.4 ± 11.4 years) and a group of 21 age-matched subjects (18 F, 3 M, age 49.3 + 10.5 years). We performed transthoracic echocardiography (Phillips iE 33) and measured serum endothelin-1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), asymmetric dimethylarginine (ADMA), endoglin and human tissue inhibitor of matrix metalloproteinase (TIMP-1) concentration.ResultsMedian serum NT-proBNP level in SSc patients was 133.5 (range 21.86–17,670 pg/ml) and was significantly higher than in controls (p = 0.0002). Moreover, the median serum ET-1 level of 1.49 (range 0.26–8.75 pg/ml) was higher in SSc patients (p = 0.002). However, no significant differences in ADMA, TIMP-1 and endoglin serum concentration between SSc patients and controls were observed. Serum NT-proBNP concentration correlated positively with echocardiographic signs of RV overload: tricuspid regurgitation pressure gradient (r = 0.38, p = 0.0004) and RV Tei index (r = 0.25, p = 0.01). ET-1 serum level correlated negatively with tricuspid annular plane systolic excursion (r = −0.4, p = 0.01) and positively with inferior vena cava diameter measured at expiration (r = 0.38, p = 0.0002). The echocardiographic signs of RV overload were significantly more pronounced in the highest NT-proBNP tertile (>195 pg/ml) group than in the lowest one (<88 pg/ml).ConclusionsSerum ET-1 and NT-proBNP, but not endoglin, ADMA and TIMP-1 levels correlating with the echocardiographic parameters of RV overload, can be considered as noninvasive indicators of RV dysfunction in SSc patients.

Membrane and Soluble Forms of Endoglin in Preeclampsia

Preeclampsia is a disease of high incidence in pregnant women which complicates pregnancy and may lead to the death of mother and baby. Preeclampsia is characterized by a series of clinical features such as hypertension and proteinuria associated with endothelial dysfunction. Although the causes of disease have not been elucidated, it has been reported that high levels of endoglin, a TGF-β auxiliary co-receptor, and a soluble form of this protein, occur respectively in the placenta and plasma of women who develop the disease. In this review, the alterations in vasculogenesis and angiogenesis that occur during preeclampsia, the cellular and molecular mechanisms that lead to increased membrane bound endoglin expression and soluble endoglin release, including hypoxia and oxidative stress, and the possible pathogenic role of soluble endoglin in this disease have been analyzed.

Identification and characterization of nodal metastases in prostate cancer patients at high risk for lymph node involvement

Aim. To investigate whether blood-based markers could be used to identify prostate cancer (PCa) patients harboring lymph node (LN) metastases. In addition, E-cadherin expression was studied within the concept of epithelial mesenchymal plasticity. Material and methods. Seventy-five patients with clinically localized PCa who underwent a superextended lymphadenectomy followed by radical prostatectomy (RP) were included in this study. Preoperative plasma/serum levels of endoglin, transforming growth factor-β1 (TGF-β1), osteopontin, vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), and E-cadherin were measured using commercially available enzyme immunoassays in 47/75 patients and correlated with clinicopathological parameters. E-cadherin expression in the diagnostic biopsies (n = 63), RP specimens (n = 75) and LN metastases (n = 106) was examined by immunohistochemical analysis. Results. Occult LN metastases were present in almost half of the patients (37/75), with a total of 106 affected LN. Preoperative levels of endoglin, TGF-β1, osteopontin, VEGF, VCAM-1 nor E-cadherin were significantly associated with LN status. Only a positive correlation between plasma endoglin and serum prostate-specific antigen was found (Spearman's r = 0.44; p = 0.002). The majority of biopsies (91.9%) and RP specimens (79.7%) showed strong E-cadherin expression, while in the LN this was found to be much weaker (28.9%). While the staining pattern in the isolated tumor cells (ITC) and micrometastases was mainly homogenous, the macrometastases showed a much more heterogeneous pattern (χ², p < 0.0001). Conclusion. In this study, none of the blood-based markers tested could be used for nodal staging in PCa, nor could E-cadherin expression in the tissue. However, the difference in E-cadherin expression pattern between the ITC/micrometastases and the macrometastases may point to another biological behavior. The specific staining pattern seen in the macrometastases could indicate an ongoing mesenchymal epithelial transition, presumed to be a mechanism for metastatic colonization. As the latter is the rate-limiting step in the metastatic process, evaluation of the E-cadherin expression pattern could have potential therapeutic implications.

Endoglin haploinsufficiency attenuates radiation-induced deterioration of kidney function in mice

Background and PurposeEndoglin is a transforming growth receptor beta (TGF-β) co-receptor, which plays a crucial role in the development of late normal tissue damage. Mice with halved endoglin levels (Eng+/- mice) develop less inflammation, vascular damage and fibrosis after kidney irradiation compared to their wild type littermates (Eng+/+ mice). This study was aimed at investigating whether reduced tissue damage in Eng+/- mice also results in superior kidney function. Material and MethodsKidneys of Eng+/+ and Eng+/- mice were irradiated with a single dose of 14 Gy. Functional kidney parameters and kidney histology were analysed at 20, 30 and 40 weeks after irradiation. ResultsEng+/- mice displayed improved kidney parameters (haematocrit, BUN) compared to Eng+/+ mice at 40 weeks after irradiation. Irradiation of Eng+/+ kidneys damaged the vascular network and led to an increase in PDGFR-β positive cells, indicative of fibrosis-promoting myofibroblasts. Compared to Eng+/+ kidneys, vascular perfusion and number of PDGFR-β positive cells were reduced in Eng+/- control mice; however, this did not further deteriorate after irradiation. ConclusionsTaken together, we show that not only kidney morphology, but also kidney function is improved after irradiation in Eng+/- compared to Eng+/+ mice.

Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Plasma levels of H2S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8-12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H2S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H2S production. These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.

Abstract 98: The biological significance of T3-regulated endoglin in human hepatoma cells.

Abstract Hypothyroidism has been associated with significantly elevated risk for hepatocellular carcinoma (HCC), although the precise underlying mechanisms remain unknown at present. Thyroid hormone (T3) and its receptor (TR) are involved in metabolism and growth. Endoglin is a T3/TR candidate target gene identified from our previous studies. Here, we demonstrated that T3 positively regulates endoglin mRNA and protein levels, both in vitro and in vivo. The thyroid hormone response elements (TRE) of endoglin were identified at positions -2114/-2004 and -2032/-1973 of the promoter region using the electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. Endoglin was downregulated in subgroups of HCC patients, and significantly associated with histology grade (negative association, p = 0.001), and this expression level was significantly associated with TRα1 in these HCC patients. Knockdown of endoglin expression in HCC cells promoted cell proliferation in the presence of T3. Moreover, endoglin stabilized p21 expression at the translational level. Based on the collective findings, we propose that endoglin is stimulated by T3 to stabilize p21, leading to the inhibition of cell proliferation. Endoglin and TRα1 levels are reduced in HCC, resulting in increased proliferative activity. Citation Format: Yang-Hsiang Lin, Ya-Hui Huang, I-Hsiao Chung, Kwang-Huei Lin. The biological significance of T3-regulated endoglin in human hepatoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 98. doi:10.1158/1538-7445.AM2013-98

Circulating Angiogenic Modulatory Factors Predict Survival and Functional Class in Pulmonary Arterial Hypertension

The diagnosis of pulmonary arterial hypertension (PAH) is frequently delayed. We hypothesized that circulating angiogenic modulatory protein levels might correspond with vascular remodeling activity and serve as sensitive biomarkers of PAH. Levels of soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR1), N-terminal brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and other biomarkers were measured in peripheral blood from 97 PAH patients, 16 first-degree relatives of idiopathic or heritable pulmonary arterial hypertension (HPAH) patients, and 56 controls, and correlated with disease, functional class, hemodynamic parameters, exercise capacity, and transplant-free survival. Endoglin expression was analyzed in lung tissues of six individuals with idiopathic or HPAH and four individuals without PAH. Levels of sEng, sVEGFR1, CRP, and NT-proBNP were elevated in Group I PAH of diverse etiologies, with sEng performing better than NT-proBNP in detecting PAH (receiver operator characteristic-area-under-the curve [ROC-AUC] of 0.82 ± 0.03 vs. 0.71 ± 0.05, P = 0.016). While sEng, sVEGFR1, and NT-proBNP correlated with New York Heart Association (NYHA) class, sEng levels were more sensitive than NT-proBNP in detecting NYHA Class I-II disease (ROC-AUC of 0.88 ± 0.05 vs. 0.67 ± 0.08, P = 0.028). sEng, sVEGFR1, CRP, and NT-proBNP predicted transplant-free survival by univariate Cox regression. After adjusting for NT-proBNP levels, each of the other three markers predicted transplant-free survival. In multivariate analysis, sEng and CRP were independent predictors of survival. Endoglin expression was markedly enhanced in the microvascular endothelium and endovascular lesions of PAH versus control lung tissues. Circulating angiogenic proteins sEng and sVEGFR1 are sensitive markers of prognosis and function in Group I PAH, including mildly symptomatic disease, and may provide unique noninvasive data reflecting underlying remodeling activity.

Variation in endoglin pathway genes is associated with preeclampsia: a case–control candidate gene association study

BackgroundPreeclampsia is a hypertensive, multi-system pregnancy disorder whose pathophysiology remains unclear. Elevations in circulating soluble endoglin (sENG) and placental/blood ENG mRNA expression antedate the clinical onset of preeclampsia. This study investigated if endoglin (ENG) pathway genetic variation was also associated with the development of preeclampsia.MethodsWe used a case–control candidate gene association design. Data from 355 white (181 preeclampsia cases/174 controls) and 60 black (30 preeclampsia cases/30 controls) women matched on ancestry, age, and parity were analyzed. Tagging single nucleotide polymorphisms (tSNPs) and potentially functional SNPs in ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2 were genotyped with iPLEX® and TaqMan®. Chi-square or Fisher’s exact tests were used to conduct allele/genotype/haplotype tests in white/black subgroups separately. Odds ratios were computed with binary logistic regression for tSNPs with significant genotype tests.ResultsOf the 49 SNPs evaluated, variation in two ENG tSNPs (rs11792480, rs10121110) and one TGFβR2 tSNP (rs6550005) was associated with preeclampsia in white women (P <0.05, each). In black women, variation in two TGFβ1 tSNPs (rs4803455, rs4803457), one TGFβR1 tSNP (rs10739778), and three TGFβR2 tSNPs (rs6550005, rs1346907, rs877572) was associated with preeclampsia (P <0.05, each). Further evaluation of ENG tSNP rs10121110 revealed that white women inheriting the AA genotype were 2.29 times more likely to develop preeclampsia compared to the GG genotype (P = 0.008, [99% CI: 1.02 to 5.13]). For black women, similar evaluation of TGFβ1 tSNP rs4803457 revealed women inheriting the CT genotype were 7.44 times more likely to develop preeclampsia than those with the CC genotype (P = 0.005, [99% CI: 1.19 to 46.41]).ConclusionsENG pathway genetic variation is associated with preeclampsia. Different ENG pathway genes may be involved in preeclampsia development among white and black women. Additional studies are needed to validate these findings and to determine if genetic variation in ENG pathway genes impacts ENG and sENG levels in preeclampsia.

Placental expression of VEGF is increased in pregnancies with hydatidiform mole: Possible association with developing very early onset preeclampsia

BackgroundHydatidiform mole is an abnormal pregnancy with over-proliferation of the placenta, which causes the dysfunction of placenta. Although more than 80% of hydatidiform moles are benign with good outcome, hydatidiform moles are associated with developing very early onset preeclampsia. However the association between hydatidiform mole and very early onset preeclampsia is unclear. Preeclampsia is associated with altered levels of angiogenic factors, like vascular endothelial growth factor (VEGF) and soluble endoglin. AimThe aim of this study is to investigate the levels of VEGF and endoglin in hydatidiform molar placenta. Study design21 placentas from complete hydatidiform mole, 9 placentas from partial hydatidiform mole and 18 placentas from gestation matched placenta were collected in this study. SubjectsThe subjects of this study are human placentas. Outcome measuresThe protein levels and mRNA levels of VEGF and endoglin were measured using immunohistochemistry, western blotting and real time PCR. ResultsThe protein levels of VEGF measured by immunohistochemistry and western blotting were significant increased, as well as mRNA levels of VEGF quantified by real time PCR in hydatidiform molar placenta in comparison to normal controls. There was no difference in the protein levels of VEGF between complete and partial hydatidiform moles. In contrast, the levels of protein and mRNA in endoglin were no difference between hydatidiform molar placenta and normal controls. ConclusionIn this study our data show that hydatidiform moles produce more VEGF than normal early pregnant placenta. The increased levels of angiogenic factors VEGF in hydatidiform moles may link to the mechanism of developing very early onset preeclampsia.

Alteration in Endoglin-Related Angiogenesis in Refractory Cytopenia with Multilineage Dysplasia

The functional mechanisms involved in angiogenesis and the potential role of endoglin (ENG), recently described as a new marker for this process, have not been explored in Myelodysplastic Syndromes (MDS). In order to gain insight in MDS angiogenesis a combined analysis in bone marrow (BM) of gene expression levels, angiogenesis-related soluble factors and functional angiogenesis-related studies was carried out. Ninety-seven MDS patients and forty-two normal BM samples were studied. The morphology of the capillary-like structures originated by two endothelial cells lines in the BM environment of patients with refractory cytopenia with multilineage dysplasia (RCMD) was different from those of the remaining MDS. In addition, the BM mononuclear cells from RCMD patients displayed over-expression of VEGF, HIF and FN1 while they showed reduced expression of ENG in contrast to the normal ENG expression of the remaining low-risk MDS and the high expression of ENG in high-risk MDS subtype. Moreover, higher soluble ENG and soluble FLT-1 levels in BM microenvironment were observed in RCMD cases, which distinguished them from other individuals. Therefore, the present study suggests that the patterns of angiogenesis are different between the MDS subtypes. The differences in angiogenesis observed in RCMD patients could be related to ENG abnormalities.

Placental endoglin levels in diamniotic-monochorionic twin gestations: Correlation with clinical and placental characteristics

ObjectiveWhile endoglin has been implicated in the pathogenesis of various complications in singleton pregnancies, its potential contribution to complications of monochorionic twinning remains largely undetermined. The aim of this study was to determine the correlation between relevant clinical and pathological variables and placental endoglin levels in diamniotic-monochorionic twin pregnancies. MethodsEndoglin expression was studied by immunohistochemistry and Western blot in a prospective cohort of 68 non-TTTS and 7 TTTS monochorionic twin placentas. Placental endoglin levels were correlated with clinical and placental characteristics associated with twin-to-twin transfusion syndrome (TTTS) and selective growth restriction, including birth weight discordance, uneven placental sharing, peripheral cord insertion and choriovascular anatomy. ResultsIn non-TTTS gestations discordant for these criteria, placental endoglin levels were significantly higher for the twin with smaller birth weight, intrauterine growth restriction, and/or abnormal ultrasound Doppler studies than for the more normal co-twin. Similarly, placental endoglin levels were significantly higher in the placental territory with smaller share and/or peripheral cord insertion in cases discordant for these placental characteristics. In TTTS gestations, placental endoglin levels tended to be higher for donor twins than for recipients. There was no correlation between endoglin levels and superficial choriovascular anastomoses. ConclusionsWhile the exact functional implications remain to be determined, our findings suggest a strong correlation between unbalanced placental endoglin levels and intertwin growth discordance in monochorionic twins.

Evaluation of the usefulness of endoglin level as a predictor of preeclampsia in pregnant women with hypertension

Preeclampsia is a pregnancy-specific syndrome that occurs after the 20 weeks of pregnancy and is characterized by hypertension and proteinuria. It complicates approximately 5-6% of all pregnancies and is a major factor in fetal and neonatal mortality The aim of this study was to evaluate serum concentration of soluble endoglin (sEng) as the predictor of preeclampsia in pregnant women with hypertension. The study was conducted at the Department of Pathology of Pregnancy (Department of Gynecology and Obstetrics, Medical University of Lodz), and the clinical ambulatory of the WSSz--M. Madurowicz (at present, WSSz--M. Pirogow) in Lodz, between 2008-2012. The Committee of Bioethics, Medical University of Lodz approved of the research (RNN/106/08/KE, May 20, 2008). The study included 86 pregnant women, between 25 and 40 weeks of pregnancy The subjects were divided into 3 groups: - Group HA--33 pregnant women with hypertension arterialis (> 140/90 mmHg) without proteinuria, --Group P--21 pregnant women with hypertension arterialis (>140/90 mmHg) with proteinuria, --Group K--32 pregnant women with normal blood pressure (< 140/90 mmHg) without proteinuria. Markings were determined with the ELISA method, using Quantikine kit. A significantly higher value of endoglin levels were found in pregnant women with preeclampsia syndrome (P) than in women with hypertension (HA) and the control group (K). Levels of endoglin in the P group was 29.70 pg/ml, 19.54 pg/ml in the HA group and 12.99 pg/ml in the K group. Elevated serum concentration of soluble endoglin (SENG) in pregnant women constitutes a risk factor for preeclampsia.

P-045 Circulating levels of soluble endoglin (CD105) in maternal plasma in preeclampsia

P-045 Circulating levels of soluble endoglin (CD105) in maternal plasma in preeclampsia

Clinical Relevance of Serum Endoglin Level in Egyptian Hepatocellular Carcinoma Patients

In hepatocellular carcinoma (HCC), preferential expression of endoglin on endothelial cells of the tumor vasculature versus neoplastic cells has led to the suggestion that it originates from the neovasculature and plays an important role in angiogenesis. Our study aimed to evaluate the role of serum endoglin in the diagnosis of HCC and to correlate it with other studied prognostic markers. Sixty hepatocellular carcinoma patients were studied, 60 cirrhotic patients and 45 matched healthy controls. Liver function tests, alpha fetoprotein (alphaFP) and serum endoglin levels were determined. The study revealed a significant increase in alphaFP and endoglin in patients with liver disease compared to controls and in HCC patients compared to cirrhotic ones. There was a positive correlation between both biomarkers and stages of HCC, whereas no significant correlation between endoglin and alphaFP or between both of them and Child Pugh's classification was seen. At a cutoff value of 20 ng/mL, the sensitivity of alphaFP was 75% and the specificity was 90%, in differentiating HCC from cirrhosis. At a 7.5 ng/mL cutoff, the sensitivity of endoglin was 70% and specificity was 65%. On combination of both biomarkers, the sensitivity was increased to 85%. Serum endoglin is a useful complementary biomarker in the diagnosis of HCC.

P 12: Chronic and oscillating high glucose induce, through oxidative stress, A “memory” effect for endoglin and NRF-2-downstream genes in endothelial cells

Background and aims: Hyperglycaemia produces endothelial dysfunction, and the so called “Metabolic Memory”, convincingly through the generation of oxidative stress. Endoglin (Eng), the TGF-β co-receptor, may drive angiogenesis and vascular remodelling in the endothelial cells, regulating two divergent effects of the TGF-β signalling: proliferative effects (through Alk1-smad1/5) or pro-apoptotic signals (through Alk5-smad2/3). Many studies have shown this role for Eng but little is known in the diabetes-associated pathologies. Recently, a correlation between the soluble form of Eng (s-Eng) and glycaemia and HbA1c has been reported as well as its involvement in diabetic nephropathy and in diabetes-associated hypertension. The goal of the present study was to evaluate if high glucose (chronic and oscillating) may induce Eng over-expression in cultured endothelial cells, and if it could be also accompanied by a “Memory” effect. Furthermore, the possible role of oxidative damage has been studied, evaluating the antioxidant intracellular defence mediated by the detoxification enzyme NQO-1, and by the oxidative stress-related protein HO-1. The effect of the antioxidant α-lipoic acid on them was also evaluated. Primary Human Umbilical Vein Endothelial cells (HUVEC) were incubated in different conditions: for 3 weeks in normal glucose (NG, 5 mmol/l), chronic high glucose (HG, 25 mmol/l), and oscillating glucose (OG, 5/25 mmol/l); for 1 week in constant 5 mmol/l glucose after being exposed for 2 weeks to continuous high glucose (25 mmol/l, HG-M) and oscillating glucose (5/25 mmol/l every 24 h, OsG-M). The impact of α-lipoic acid (ALA, 62.5 μM) was also measured. mRNA and protein levels of Nrf2-dependent ARE-responsive genes (hmox1 and nqo1) and Endoglin were measured using real-time PCR, Western blot and quantified in the standard method. All analyses were evaluated for statistical significance. Eng mRNA expression was more elevated in oscillating than in high glucose (NG-OG, p=0.006; NG-HG, p=0.01). Endoglin protein level was found to be upregulated in oscillating glucose (3.5-fold) respect to basal conditions. These increases in Endoglin were reduced with α-lipoic acid treatment both in mRNA (HG-HG+, r=0.98, p=0.001) and protein levels. Elevation in mRNA expression of cytoprotective genes hmox-1 (NG-OG, p=0,005) and nqo1 (NG-OG, p=0,007) were found, but the ALA-treatment induced a more distinct expression of HO-1 (2-fold) and NQO1 (2.5-fold) gene levels, in oscillating glucose. The similar trend was also assessed for protein expression. A “memory” effect was also detected for nqo-1 (NG-OsG-M, p=0,01), hmox-1 (NG-OsG-M, p=0,05) and Eng (NG-OsG-M, p=0,04). These data show that both oscillating and high glucose induce expression of Eng, suggesting the TGF-β signalling implication on endothelial cells regulation. The memory effect was assessed for Eng, hmox1 and nqo1, being oscillating glucose more dangerous. Moreover, the ALA treatment induced expression of Nrf-2 related genes suggesting a role for oxidative stress in such phenomenon. Finally, the findings establish Eng as a critical regulator of endothelial cells in oscillating and high glucose, and that Lipoic Acid positively influences Nrf2-driven gene expression of defence mechanisms against ROS.

Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review

HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome is serious for the mother and the offspring. HELLP occurs in 0.2-0.8% of pregnancies and in 70-80% of cases it coexists with preeclampsia (PE). This review concerns the pathogenetic mechanisms of HELLP syndrome with an emphasis on differences between HELLP and early onset PE. The syndromes show a familial tendency. A previous HELLP pregnancy is associated with an increased risk of HELLP as well as PE in subsequent pregnancies, indicating related etiologies. No single world-wide genetic cause for excessive risk of HELLP or PE has been identified. Combinations of multiple gene variants, each with a moderate risk, with contributing effects of maternal and environmental factors, are probable etiological mechanisms. Immunological maladaptation is the most probable trigger of the insult to the invading trophoblast. This insult occurs early in the first trimester, as indicated by marker molecules in maternal blood. The levels of fetal messenger RNAs in maternal blood at gestational weeks 15-20 are significantly more abnormal in HELLP than in PE, suggesting that the insult is more extensive in HELLP. High levels of HLA-DR in maternal blood in women with HELLP may suggest a similarity to the rejection reaction. In third trimester placentas, gene derangement is more extensive in HELLP. Anti-angiogenic factors released into maternal blood induce the maternal syndromes. Maternal blood levels of anti-angiogenic sFlt1 are similar, but endoglin and Fas Ligand levels are possibly higher in HELLP than in PE. These factors trigger the vascular endothelium, resulting in an enhanced inflammatory response which is stronger in HELLP. Activated coagulation and complement, with high levels of activated leucocytes, inflammatory cytokines, TNF-α, and active von Willebrand factor, induce thrombotic microangiopathy with platelet-fibrin thrombi in microvessels. The angiopathy results in consumption of circulating platelets, causes hemolysis in affected microvessels and reduces portal blood flow in the liver. Placental Fas Ligand damages hepatocytes, resulting in periportal necrosis. In about one half of women with HELLP, activation of coagulation factors and platelets precipitates disseminated intravascular coagulation, which in a minority becomes uncompensated and contributes to life-threatening multiorgan failure.

Plasma Concentrations of Soluble Endoglin versus Standard Evaluation in Patients with Suspected Preeclampsia

BackgroundThe purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks.Methods and FindingsData from all women presenting at <34 weeks for evaluation of preeclampsia with singleton pregnancies (July 2009−October 2010) were included in this analysis and sEng levels were measured at presentation. Data was analyzed for 170 triage encounters and presented as median {25−75th centile}. Thirty-three percent of patients (56 of 170) experienced an adverse outcome. sEng levels (ng/ml) were significantly elevated in patients who subsequently experienced adverse outcomes compared to those who did not (32.3 {18.1, 55.8} vs 4.8 {3.2, 8.6}, p<0.0001). At a 10% false positive rate, sEng had higher detection rates of adverse outcomes than the combination of highest systolic blood pressure, proteinuria and abnormal laboratory tests (80.4 {70.0, 90.8} vs 63.8 {51.4, 76.2}, respectively). Subjects in the highest quartile of sEng were more likely to deliver early compared to those in the lowest quartile (HR: 14.96 95% CI: 8.73−25.62, p<0.0001). Natural log transformed sEng correlated positively with log sFlt1 levels (r = 0.87) and inversely with log PlGF levels (r = −0.79) (p<0.0001 for both). Plasma sEng had comparable area under the curve for prediction of adverse outcomes as measurement of sFlt1/PlGF ratio (0.88 {0.81, 0.95} for sEng versus 0.89 {0.83, 0.95} for sFlt1/PlGF ratio, p = 0.74).ConclusionsIn women with suspected preeclampsia presenting prior to 34 weeks of gestation, sEng performs better than standard clinical evaluation in detecting adverse maternal and fetal outcomes occurring within two weeks of presentation. Soluble endoglin was strongly correlated with sFlt1 and PlGF levels, suggesting common pathogenic pathways leading to preeclampsia.

Early pregnancy screening for hypertensive disorders in women without a‐priori high risk

To evaluate the performance of mean arterial pressure, uterine artery pulsatility index and soluble endoglin level alone or in combination in screening for hypertensive disorders in pregnant women without a-priori high risk. This was a nested case-control study of women with singleton pregnancies without a-priori high risk who developed pregnancy-induced hypertensive complications. Women were enrolled into the study at 11-14 weeks' gestation, when mean arterial pressure and uterine artery pulsatility index were recorded and a blood sample was taken for measurement of soluble endoglin. Women were followed up in the clinic to detect development of any hypertensive disorder. Each affected case was matched with two normotensive control women with uncomplicated pregnancies that resulted in phenotypically normal infants. Mean values for each variable were compared between cases and controls. Sensitivities, positive predictive values and negative predictive values at fixed specificity were derived from receiver-operating characteristics (ROC) curves. During the study period, 2120 patients were examined. Of these, 170 (8.02%) were excluded because they were lost to follow-up and in 52 (2.45%) there was fetal death or miscarriage before 24 weeks' gestation. Thus, 1898 cases formed the cohort population. Of these, 89 (4.69%) patients developed complications (study group), including 16 (0.84%) cases with early pre-eclampsia (PE), 60 (3.16%) with late PE and 13 (0.68%) with gestational hypertension (GH). There were 49 (2.58%) cases of spontaneous preterm delivery before 34 weeks. The rest of the cohort population (1760 (92.73%) patients, the base cohort) were not affected by PE or GH. The control group comprised 178 patients. The best model for the prediction of any of the types of hypertensive disorders was one that combined mean arterial pressure with soluble endoglin (area under the ROC curve (AUC), 0.83). The predictive value of the three combined markers was highest for screening for early and late PE (AUC, 0.86 and 0.83, respectively). When each marker was considered alone, the highest prediction of any type of hypertensive disorder was achieved by mean arterial pressure (AUC, 0.73). Sensitivity was lowest for detection of GH when screening both by individual and by combined markers. First-trimester screening can be useful in predicting women at high risk of developing hypertensive disorders of pregnancy but more prospective longitudinal studies are needed.

Maternal serum endoglin as an early marker of pre-eclampsia in high-risk patients

BackgroundPre-eclampsia is a potentially serious condition that still accounts for significant morbidity and mortality for the affected mother and neonate. Although the pathogenesis is not fully understood, it is now widely accepted that vascular endothelial dysfunction is the most important and principal event in the pathophysiology of the disease. The aims of our study were to compare serum soluble endoglin levels at week 13 in normotensive pregnant women and in high-risk women, to determine whether the maternal plasma soluble endoglin concentration at 26 weeks is increased in pregnancies that subsequently develop pre-eclampsia, and to identify if soluble endoglin measurement improves the results of screening for pre-eclampsia.MethodsThis work was conducted in 60 healthy pregnant controls and 110 pregnant women at high risk for pre-eclampsia. Gestational age was confirmed by date of last menstrual period and first trimester ultrasound. The time of onset of pre-eclampsia was defined as the time of first elevated blood pressure or urinary protein measurement leading to the diagnosis. Blood samples were collected for measurement of soluble endoglin and other routine laboratory tests, including measurement of urinary proteins. Serum soluble endoglin was estimated by sandwich enzyme-linked immunosorbent assay.ResultsThere was a highly significant increase in serum soluble endoglin in high-risk women compared with controls at week 13 (P < 0.001). Further determination of soluble endoglin revealed a more significant increase in women who developed early-onset pre-eclampsia compared with those who developed late-onset pre-eclampsia. Moreover, a significant positive correlation was found between soluble endoglin and both diastolic blood pressure and total urinary protein, ie, severity of pre-eclampsia.ConclusionEstimation of serum soluble endoglin at gestational week 13 could be used as a sensitive screening test for women at high risk of developing pre-eclampsia prior to onset of its clinical manifestations, which could potentially improve the outcome of pregnancy.

Prognostic importance of markers for inflammation, angiogenesis and apoptosis in high grade glial tumors during temozolomide and radiotherapy

IntroductionAngiogenesis, inflammation and apoptosis have an important place in the carcinogenesis of high-grade gliomas (HGG). We evaluated the postoperative levels and the prognostic importance of tumor necrosis factor-alpha (TNFα), interleukin 6 (IL6), endoglin (CD105), vascular endothelial growth factor (VEGF), M65 and M30 as markers of inflammation, angiogenesis and apoptosis in patients with HGG. Methods and resultsPostoperative pretreatment sera were collected from 44 newly diagnosed patients with HGG. The control group was also consisted of 44 healthy people. The median age of all patients with HGG was 59 (range: 30–80). Temozolomide concurrent with radiotherapy was given to 37 patients. Thereafter 24 patients received consolidation temozolomide monotherapy. Mean chemotherapy cycle was 4.2. Progression free survival and overall survival were 6 (95% CI; 5.16–6.83) and 16months (95% CI; 13.07–18.93) respectively in patients treated with concurrent chemoradiotherapy and consolidation chemotherapy. Relative to the control cohort endoglin (p=0.000) and TNFα (p=0.000) levels were significantly lower; however VEGF (p=0.030) levels were higher in the patient group. In contrast, there were no significant change in IL-6 levels and the plasma apoptotic markers M65 (p=0.085) and M30 (p=0.292). In separate log rank tests, these biological markers did not correlate with survival. Discussion and conclusionIn HGG, a significant decrease in endoglin and TNFα levels was observed, while VEGF levels were significantly increased postoperatively. However, with the power from this patient population, no correlation with survival was observed.