Serum Ang-2 Research Articles

Angiopoietin-2 Is an Early Indicator of Acute Pancreatic-Renal Syndrome in Patients with Acute Pancreatitis.

Within the first week of the disease, acute kidney injury (AKI) is among the most common causes of mortality in acute pancreatitis (AP). Recently, serum angiopoietin-2 (Ang-2) has been associated with hyperdynamic state of the systemic circulation. The aim of this study was to examine the associations between Ang-2 and the clinical AP severity during the first 72 hours of the disease, and organ disfunction, including AKI. Methods. Study included patients admitted to the surgery ward, diagnosed with AP. AKI was diagnosed according to KDIGO guidelines and renal failure according to modified Marshall scoring system. Ang-2 was determined in serum with ELISA. Results. AP was classified as mild (MAP) in 71% of patients, moderately severe (MSAP) in 22%, and severe (SAP) in 8%. During the first 72 hours of AP, 11 patients developed AKI and 6 developed renal failure. Ang-2 at 24, 48, and 72 hours following the onset of AP symptoms significantly predicted SAP and MSAP, as well as AKI and renal failure. Also, Ang-2 significantly correlated with acute phase proteins as well as with the indicators of renal disfunction. Conclusions. Serum Ang-2 may be a relevant predictor of AP severity, in particular of the development of AP-renal syndrome.

Diagnostic Value of Serum Angiopoietin-2 in Patients with Hepatocellular Carcinoma

Background and study aim: Hepato-cellular carcinoma (HCC) is a hypervascular tumor and its progression is known to be closely related to angiogenesis. Angio-poietin-2 (Ang-2) is one of the angiogenic factors that may have a diagnostic value in HCC. Alpha-fetoprotein (AFP) serum levels are used for screening for HCC with limited success. This study aimed to evaluate diagnostic value in using angio-poietin-2 as a serum marker in HCC patients. Patients and Methods: 50 patients with HCC (G1), 20 patients with liver cirrhosis (G2), and 20 healthy control persons (G3) were included in this study. Serum AFP and Ang-2 levels were measured by enzyme-linked immunosorbent assay. Results: Serum Ang-2 levels in the HCC group (1523.54±886.46 pg/ml) was highly significantly elevated as compared to those with cirrhotic liver (222.55±153.60 pg/ml) and controls (138.35±54.09 pg/ml). The Ang-2 levels were significantly different between patients with liver cirrhosis and controls. In HCC patients, the serum Ang-2 levels in patients with portal vein (PV) thrombosis (n=7, 2164.0±960.85 pg/ml) and with large HCC (>5cm in diameter) (n=17, 2017.70±903.06 pg/ml) were significantly higher than those without PV thrombosis (n=43, 1274.47±727.56 pg/ml) and with small HCC (≤5cm in diameter) (n=33, 1268.97±773.93 pg/ml), while the serum AFP levels in patients with portal vein (PV) thrombosis (961.05±1007.70 ng/ml) and with large HCC (>5cm in diameter) (1000.81±1079.57 ng/ml) were not significantly higher than those without PV thrombosis (500.24±733.07 ng/ml) and with small HCC (437.87±611.02 ng/ml). Conclusion: Combined measurement of serum AFP and Ang-2 significantly increases the sensitivity and specificity of HCC detection rather than using of AFP or Ang-2 separately.

Prognostic significance of the angiopoietin-2/angiopoietin-1 and angiopoietin-1/Tie-2 ratios for early sepsis in an emergency department.

IntroductionThis study was performed to assess the early diagnostic, risk stratification, and prognostic value of the angiopoietin-2/angiopoietin-1 ratio (Ang-2/Ang-1) and angiopoietin-1/tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 ratio (Ang-1/Tie-2) and to compare these factors with procalcitonin (PCT) and the Mortality in Emergency Department Sepsis (MEDS) score in patients with early sepsis in the emergency department (ED).MethodsConsecutive patients with sepsis (n = 440) were enrolled in this study. They fulfilled the systemic inflammatory response syndrome (SIRS) criteria and were admitted to the ED of Beijing Chao-yang Hospital between August 2014 and February 2015. The control group consisted of 55 healthy blood donors. The patients were categorized into four groups: SIRS, sepsis, severe sepsis, and septic shock. Serum Ang-1, Ang-2, Tie-2, and PCT were measured, and the MEDS score was calculated upon ED arrival. The prognostic values of Ang-2/Ang-1, Ang-1/Tie-2, Ang-1, Ang-2, and Tie-2 were compared with the PCT and MEDS scores. All patients were followed for 28 days.ResultsUpon admission, the median levels of the serum Ang-2 level and Ang-2/Ang-1 ratio increased and the serum Ang-1 levels and Ang-1/Tie-2 ratios decreased with the severity of sepsis. The areas under the receiver operating characteristic curves of the Ang-2/Ang-1 and Ang-1/Tie-2 ratios were greater than those of the Ang-1, Ang-2, and PCT levels and MEDS scores in the diagnosis and prediction of 28-day mortality due to sepsis. Ang-2/Ang-1 was significantly higher and Ang-1/Tie-2 was significantly lower in nonsurvivors than in survivors at the 28-day follow-up examination. Ang-2/Ang-1, Ang-1/Tie-2, and MEDS score were found to be independent predictors of 28-day mortality in patients with sepsis. The levels of serum Ang-1, Ang-2, and Tie-2 were positively correlated with each other. The ratios of Ang-2/Ang-1 and Ang-1/Tie-2 were positively and negatively correlated, respectively, with the MEDS score in every septic group.ConclusionsThe Ang-2/Ang-1 and Ang-1/Tie-2 ratios are valuable for risk stratification in patients with sepsis and are associated with the poor clinical outcome of early sepsis in the ED.

Abstract 18963: Over-expression of Angiopoietin-2 in Human Patients With Continuous-flow Left Ventricular Assist Devices Induces Abnormal Angiogenesis and Predicts Gastrointestinal Bleeding Events

Arteriovenous malformations are common in patients with Continuous-Flow Left Ventricular Assist Devices (LVAD) and may reflect deregulation of angiogenesis. Angiopoietin-2 (Ang-2) is a stimulator of angiogenesis produced by endothelial cells in response to thrombin. In this study, we evaluate Ang-2 expression in patients with LVAD compared with stable heart failure (HF) or orthotopic heart transplant (OHT) and test the hypothesis that elevated Ang-2 in patients with LVAD leads to increased angiogenesis. Blood samples were taken from 79 patients (n= 21 HF, 41 LVAD, 17 OHT) during routine heart catheterization. Ang-2 was measured by ELISA and thrombin was measured by Western Blot. Cultured human umbilical vein endothelial cells (HUVECs) were incubated with plasma from each patient and Ang-2 expression was measured by RT-PCR. HUVECs were then incubated on Matrigel with serum from each patient in the presence or absence of an Ang-2 blocking antibody and tube formation was measured by microscopy. Also, vena caval endothelial cells were isolated from discarded guide wires used during catheterization and Ang-2 expression was measured by quantitative immunofluorescence. In patients with LVAD vs. HF or OHT, Ang-2 was elevated in both serum (12.3±9.6, 4.5±2.1, and 4.9±2.0 ng/mL respectively, p<0.01) and endothelial cells (56.3±14.1, 31.3±4.2, 35.0±11.2 AU respectively, p<0.05). On Matrigel, serum from patients with LVAD vs. HF or OHT induced increased tube formation (57.1±3.2, 39.2±7.1, 34.7±5.1 tubes per low power field respectively, p<0.05) and this elevation normalized with Ang-2 blocking antibody. Plasma from patients with LVAD vs. HF or OHT induced Ang-2 gene over-expression in HUVECs (1.6±0.4, 1.0±0.3, 0.6±0.2 RQ respectively, p<0.01) and was associated with higher plasma thrombin. In patients with LVAD, serum Ang-2 >10 ng/mL was associated with a higher 3 month risk of GI bleeding vs. Ang-2 <10 ng/mL (30% vs. 0%, p<0.01). Therefore, we conclude that over-expression of Ang-2 in patients with LVAD induces increased angiogenesis and predicts GI bleeding events. Thrombin is increased in patients with LVAD and their plasma induces Ang-2 over-expression in vitro . Therefore, Ang-2 overexpression may contribute to AVM formation in patients with LVAD.

Combination of serum angiopoietin-2 and uterine artery Doppler for prediction of preeclampsia

The aim of this study was to determine the predictive value of the combination of serum angiopoietin-2 (Ang-2) levels and uterine artery Doppler for the detection of preeclampsia in women at 16-18 weeks of gestation and to identify other pregnancy complications that could be predicted with these combined tests. Maternal serum Ang-2 levels were measured, and uterine artery Doppler was performed in 400 pregnant women. The main outcome was preeclampsia. The predictive values of this combination were calculated. Twenty-five women (6.3%) developed preeclampsia. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of uterine artery Doppler combined with serum Ang-2 levels for the prediction of preeclampsia were 24.0%, 94.4%, 22.2% and 94.9%, respectively. For the prediction of early-onset preeclampsia, the sensitivity, specificity, PPV and NPV were 57.1%, 94.1%, 14.8% and 99.2%, respectively. Patients with abnormal uterine artery Doppler and abnormal serum Ang-2 levels (above 19.5 ng ml(-1)) were at higher risk for preterm delivery (relative risk=2.7, 95% confidence interval 1.2-5.8). Our findings revealed that the combination of uterine artery Doppler and serum Ang-2 levels at 16-18 weeks of gestation can be used to predict early-onset preeclampsia but not overall preeclampsia. Thus, this combination may be a useful early second trimester screening test for the prediction of early-onset preeclampsia.

Serum Angiopoietin-2 and C-reactive protein as biomarkers of acute exacerbations of chronic obstructive pulmonary diseases

ObjectivesTo evaluate the role of serum Angiopoietin-2 and C-reactive protein as blood biomarkers of acute exacerbation of COPD and to assess if they have a relationship with the severity of COPD and the severity grades of exacerbations. BackgroundRecently, Angiopoietin-2 (Ang-2) was identified as a ligand of the endothelial receptor tyrosine kinase, Tie-2. Ang-2 is an Angiopoietin-1 antagonist that plays a role in vascular destabilization and remodeling, which may increase in some diseases. However, serum Ang-2 levels have not been evaluated in patients with COPD.In this study, we examined serum Ang-2 concentrations in patients with COPD exacerbations and in patients with stable COPD. MethodsThis study was conducted on 36 COPD patients in acute exacerbation, 20 patients with stable COPD and 20 healthy subjects (control group), they were selected from the Shibin-Elkoom Chest Hospital from February 2013 to October 2013. All subjects were subjected to detailed clinical history, thorough clinical examination, Modified British Medical Research Council (mMRC) questionnaire and the COPD Assessment Test questionnaire (CAT) to assess symptoms, plain chest-X-ray (postero-anterior and lateral views). Blood sample for the measurement of Angiopoietin-2 and C-reactive protein by ELISA. ResultsSerum concentrations of Ang-2 and CRP were significantly higher in patients with acute exacerbations of COPD than in those with stable COPD or control subjects. Ang-2 was significantly positively correlated with serum CRP levels but negatively correlated with PaO2 in patients with exacerbations. ConclusionSerum levels of Ang-2 and CRP are significantly elevated during acute exacerbations of COPD, as compared with stable COPD.

Prognostic significance of serum vascular endothelial growth factor and Angiopoietin-2 in patients with lung cancer.

Vascular endothelial growth factor (VEGF) and Angiopoietin-2 (Ang-2) are major angiogenic mediators in neovascularization process. In current literature both biomarkers are discussed separately and only for non-small cell lung cancer (NSCLC). So in this study we aimed to examine them together for both cell types NSCLC and small cell lung cancer (SCLC). 100 patients with lung cancer were enrolled to this single center study. 87 of patients were diagnosed with NSCLC including 28 adenocarcinomas and 59 squamous cell cancers and 13 were SCLC. Results were compared with 30 healthy volunteers. Pre-treatment serum VEGF and Ang-2 levels were measured by using ELISA method. While serum Ang-2 levels were higher in patients than healthy controls (23395 pg/mL vs. 4025 pg/mL, p< 0.001), VEGF levels didn't differ (2308 pg/mL vs. 2433 pg/mL, p> 0.05). There was no difference between cases with SCLC and NSCLC in terms of Ang-2. But serum VEGF values were significantly lower in SCLC than NSCLC and control groups. None of these mediators were correlated with cell type, tumor size, TNM staging, performance status and operability. VEGF levels were higher in patients with chronic obstructive pulmonary disease (COPD), but it was not significant. Three cut of values were determined according to sensitivity and specificity by using youden index. They were 8515.73 pg/mL (sensitivity 78%, specificity 76%), 7097 pg/mL (sensitivity 80%, specificity 70%) and 11063.48 pg/mL (sensitivity 76%, specificity 70%). Patients with SCLC had shorter survival time above cut-off values (p> 0.05). VEGF and Ang-2 showed a weak positive correlation (p= 0.1 and r= 0.638). In conclusion, serum VEGF wasn't useful to predict lung cancer, prognosis or cell type. Albeit Ang-2 was higher in patients with lung cancer without any effect on survival. Due to the heterogeneity of the studies done with serum measurement Ang-2 on tumor tissue should be more meaningful.

High Angiopoietin-1 levels predict a good functional outcome within 72 h of an aneurysmal subarachnoid hemorrhage: A prospective study from a single center

BackgroundThe consequences of aneurysmal subarachnoid hemorrhage (aSAH) are lifelong and fatal. Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) play an important role in the regulation of vascular structure and function. Our study examined the association between angiopoietin levels and functional outcomes among aSAH patients. MethodsWe enrolled 37 aSAH patients and 39 controls (matched on age and sex) at the Department of Neurosurgery in Tianjin Medical University General Hospital. Serum Ang-1, Ang-2, and Tie-2 levels were collected at 8, 24, and 72hours post-hemorrhage. After a 3-month follow-up period, patient outcomes were evaluated using the Glasgow Outcome Score (GOS). Logistic regression examined the association between angiopoietin levels and outcomes (good [GOS: 4–5] vs. poor [GOS: 1–3]). ResultsaSAH patients had higher levels of Ang-1 at 8hours post-hemorrhage compared to controls. Among aSAH patients, Ang-1 levels at 8, 24, and 72hours post-hemorrhage were higher among patients with a good outcome. Compared to patients with low Ang-1 levels, high Ang-1 levels at 72hours post-hemorrhage were associated with a good outcome. ConclusionsHigh Ang-1 levels were associated with a good functional outcome after aSAH. Abnormal angiopoietin levels may disrupt the blood–brain barrier and contribute to functional outcomes in aSAH patients.

Angiopoietins predict long-term outcomes after aneurysmal subarachnoid hemorrhage during an early period

To evaluate the association between serum levels of angiopoietins (Ang) during an early period (within 72 h) and clinical outcomes after aneurysmal subarachnoid haemorrhage (aSAH). This prospective study was conducted at Department of Neurosurgery, Tianjin Medical University General Hospital. Blood samples from 37 aSAH patients were collected at 8 h (or < 8 h), 24 h, 72 h after an onset of SAH. The serum levels of Ang-1, Ang-2 and Tie-2 were measured by enzyme-linked immunosorbent assay (ELISA). They were followed up for 3 months by Glasgow outcome score extended (GOSE). Those with GOSE > 5 were counted as a good outcome while those with GOSE ≤ 5 had a poor outcome. A total of 37 patients with aSAH and 39 healthy controls (HC) were enrolled. The aSAH patients showed a significant rise of Ang-1 within 8 h as compared with HC. The outcomes were good (n = 15) and poor (n = 22). Serum Ang-1 at 8 h (or < 8 h), 24 h and 72 h in good outcomers showed significantly higher than that in poor outcomers [(52 ± 24) vs (37 ± 17) mg/L, (62 ± 26) vs (45 ± 17) mg/L, (107 ± 27) vs (72 ± 18) mg/L]. The serum level of Ang-1 at 8 h and 24 h was one of independent risk factors for aSAH patients by multiariable Logistic regression analysis [adjected OR (95% CI) 1.095 (1.015-1.181) and 1.109 (1.016-1.211)] (P < 0.05). High serum level of Ang-1 during an early period (within 72 h) was associated with good outcomers (r = 0.627, P < 0.001). The serum levels of angiopoietins are significantly altered in aSAH patients, especially higher in good outcomers. And abnormal levels of angiopoietins may affect early brain injury (EBI) after SAH, structural integrity and recovery of blood-brain barrier (BBB) and long-term outcomes in aSAH patients.

Prognostic value of pro-inflammatory cytokine and pro-angiogenesis factor in differentiating malignant from benign exudative effusion.

The precise mechanism of pathogenesis in exudation of effusions is uncertain. Released factors in inflammation and malignancy of pleura are related to incremented permeability of the micro-pleural vessels. Angiopoietins (Ang) take part in development of angiogenesis and pleural inflammation. Interleukin-8 (IL-8) influences proliferation and tumor angiogenesis and it is expressed in cancer. The aims of this study were to investigate the relationship between inflammation, angiogenesis and etiologies of exudative effusions, and to evaluate the diagnostic value in differentiating malignant from benign. The study includes 49 pleural fluid (PF) samples. Ang-2 and IL-8 in PF and serum were estimated. Ten patients were transudative and 39 patients were exudative fluid, subdivided into 16 benign and 23 malignant effusion. Ang-2 and IL-8 either fluid level or ratio were in significantly high in exudative more than in transudative fluid (P = 0.002). Ang-2 and IL-8 in PF were in high level than in serum of exudative and transudative. Ang-2 fluid level and ratio were significantly high in benign exudative effusion (P = 0.01, P = 0.05, respectively), while IL-8 level was significantly high in malignant exudative effusion (P = 0.04). Cut-off points for PF Ang-2 and IL-8 in differentiating malignant from benign exudative were 15.67 ng/mL, 325.54 pg/mL, respectively. Our results support the evidence that angiogenesis and inflammatory pathways are linked, and that inflammation and vascular permeability of pleura constitutes the pathogenic basis of the majority of exudative effusion.

Serum angiopoietin-2 is associated with angiopathy in type 2 diabetes mellitus

PurposeThe aim of the present study was to investigate the association of serum levels of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) with angiopathy in type 2 diabetes mellitus (T2DM). MethodsThe group studied comprised of 120 patients with T2DM (68 males and 52 females), included macroangiopathy complications, microvascular disease and diabetic without vascular disease. The control group consisted of 50 healthy blood donors. Ang-1, Ang-2, fasting plasma glucose (FBG), fasting insulin (FINS) and HbA1c were assessed. ResultsThe serum Ang-2 levels of T2DM patients with angiopathy were found to be significantly higher compared to patients without angiopathy. Ang-2 levels were significantly positively correlated with homeostasis model assessment for insulin resistance (HOMA-IR) and glycosylated hemoglobin A1c (HbA1c) (r=0.577 and 0.504, respectively, P<0.01). In contrast, there was no significant correlation between Ang-1 levels and HOMA-IR (P>0.05). In multivariable logistic regression analysis, Ang-2 levels (P=0.02) were found to be independently associated with patients with T2DM angiopathy. ConclusionsAn association between the Ang-2 and T2DM with vascular complications was found.

Urinary angiopoietin-2 is associated with albuminuria in patients with type 2 diabetes mellitus.

Aims. To evaluate the levels of angiopoietin-1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF) in serum and urine, and their association with albuminuria in patients with type 2 diabetes mellitus. Methods. In 113 type 2 diabetic patients with normoalbuminuria, microalbuminuria, and macroalbuminuria and 30 healthy controls, the levels of Ang-1, Ang-2, and VEGF in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). Results. Urinary and serum levels of Ang-2 were significantly higher in diabetic patients with normoalbuminuria than in healthy controls. Increased urinary Ang-2 level was positively associated with the degree of albuminuria. Urinary Ang-1 levels were significantly higher in normoalbuminuria patients and lower in macroalbuminuria patients than in controls. The levels of urinary VEGF increased in the albuminuria subgroup, though serum levels of Ang-1 and VEGF did not change. Urinary Ang-2 levels were correlated positively with albuminuria and negatively with glomerular filtration rate (GFR). Stepwise multiple regression analysis identified albuminuria (P < 0.001) and GFR (P = 0.001) as significant predictors of urinary Ang-2. Conclusions. Our data suggest that urinary Ang-2 is stepwise increased with renal damage in patients with type 2 diabetes mellitus and is associated with albuminuria.

Serum Angiopoietin-2 as Marker of Plasma Leakage in Dengue Viral Infection

Background. The immunopathology of DHF/DSS is yet completely understood. Angiopoietin-2 (Ang-2) produced by endothelial cell could promote vascular leakage by disrupting endothelial junction. Few studies reported the role of Ang-2 in dengue viral infection. Objective. To study the role of Ang-2 in promoting vascular leakage in dengue viral infection. Methods. Prospective cohort study conducted at Prof. Dr. R.D. Kandou, Pancaran Kasih and R.W. Mongonsidi General Hospitals in Manado, from March 2013 to October 2014. Children, aged 1-15 years old, with the diagnosis of dengue viral infection according to 1997 World Health Organization (WHO) criteria [Dengue Fever (DF), Dengue Hemorrhagic Fever (DHF), Dengue Shock Syndrome (DSS)],were recruited consecutively. Written informed consent was obtained from parents or legal guardian. Blood samples were obtained at the time of diagnosis and 48 hours after, evaluated for complete blood counts, albumin, NS-1, Ig M, Ig G anti-dengue, and Ang-2. Results. During the study period, there were 119 children with dengue viral infections (39 DF, 39 DHF, 41 DSS). Patient’s characteristics: female predominance, age between 1.5-8.5 years old, well nourished, and mean albumin level were less than ≤3.5 gr% in the DHF and DSS group. Ang-2 level at admission were 2,486.21 pg/dl, 3,194.95 pg/dl and 4,005.32 pg/dl in DF, DHF and DSS group, respectively. Anova test analyses shows significant differences in serum Ang-2 level at admission between DF, DHF and DSS group (p<0.0001). Between those groups, DSS group had the highest level of Ang-2, followed with DHF and DF. Discussion. Mean albumin level were 3.88 gr%, 3.39 gr% and 2.63gr% in DF, DHF and DSS group, respectively. This results shows increasing plasma leakage with increasing severity of dengue viral infection. Increasing level of Ang-2 can promote blood vessels instability therefore causing increased vascular permeability and subsequent plasma leakage. In this study, we found significant elevation of serum Ang-2 in patiens with DSS compared to DHF and DF but the difference was not significant between DF and DHF group. Conclusions. Angiopoietin-2 contributes in transient systemic vascular leak in dengue viral infection.

Serum Angiogenesis Markers and Their Correlation with Ultrasound-Detected Synovitis in Juvenile Idiopathic Arthritis.

Synovial angiogenesis is considered to be an important early step in the pathogenesis of juvenile idiopathic arthritis (JIA). In this study we assessed levels of angiogenic markers in serum or synovial fluid and their possible relevance to disease activity or degree of ultrasound signs of synovial inflammation and angiogenesis in early JIA. The concentration of vascular endothelial growth factor (VEGF), its soluble receptors 1 and 2 (sVEGF-R1, sVEGF-R2), and angiopoietins 1 and 2 (ANG-1, ANG-2) were evaluated in 43 JIA patients and 23 healthy controls. Synovial angiogenesis was assessed by means of Power-Doppler Ultrasonography (PDUS), according to the fourth-grade vascularity scale. VEGF and its receptors' (sVEGF-R1, sVEGF-R2) serum levels were significantly higher in JIA patients (p = 0.002). We found large variation in serum ANG-1 and ANG-2 levels. The PDUS imaging identified increased synovial microvascular blood flow in 15 (35.7%) examined JIA children. Intensity of joint vascularization correlated with higher serum VEGF and its levels was lowest in grade 0 and highest in grade 3 (p < 0.007 and p < 0.001, resp.). In conclusion, the high correlation between synovial microvascular blood flow, serum angiogenic proteins, and symptoms of synovitis may indicate its important role in pathogenesis of JIA.

Type 2 Diabetes and Cardiovascular Risk in Women

Type 2 Diabetes and Cardiovascular Risk in Women

CSF Levels of Angiopoietin-2 Do Not Differ between Patients with CSF Fluid Leakage Syndrome and Controls.

CSF abnormalities have been reported in CSF leakage syndrome. However, the mechanism for these CSF changes is actually unknown and they may indicate impaired CSF flow or blood-CSF barrier. Angiopoietin-2 (Ang-2), a protein which is expressed and released by endothelial cells, has been associated with increased vascular permeability. In the assumption that CSF changes are due to an impaired blood-CSF barrier, we hypothesized that subjects with persistent CSF leakage may have increased CSF Ang-2 levels. We enrolled 10 subjects with a clinically definite diagnosis of persisting CSF leakage syndrome and 10 control subjects. In CSF analyses, CSF to serum albumin ratio (Qalb) was the most frequently increased parameter indicating a disturbed blood-CSF barrier function. Comparison of the mean CSF Ang-2 levels, CSF to serum Ang-2 ratio (QAng-2), and QAng-2/Qalb between the control and CSF leakage patients did not show any significant difference. We suggest that the increase of Qalb results from a low CSF flow. Future studies with phase contrast-MRI in conjunction with CSF analyses before and after epidural blood patch treatment are required to address this question. It would be of particular interest whether Qalb can be used as a marker for successful nontargeted epidural blood patch treatment.

Tumor Necrosis Factor-Alpha and 8-Hydroxy-2'-Deoxyguanosine are Associated with Elevated Urinary Angiopoietin-2 Level in Type 2 Diabetic Patients with Albuminuria

Background/Aims: We previously showed that urine and serum Angiopoietin-2 (Ang-2) levels increased significantly with the degree of albuminuria in diabetes patients, but the reasons remain unclear. Consequently we aimed to determine whether there was an association between Ang-2, inflammatory cytokines (TNF-α and IL-18) and reactive oxygen species (8-OHdG and SOD) in type 2 diabetes patients with albuminuria. Methods: This retrospective study evaluated 113 patients with type 2 diabetes and normoalbuminuria, microalbuminuria, or macroalbuminuria and 30 healthy controls. Serum and urine TNF-α, IL-18 and 8-OHdG levels were measured by ELISA. Superoxide dismutase (SOD) activity was determined by spectrophotometry. Results: Serum and urine TNF-α, IL-18 and 8-OHdG levels increased significantly with the degree of albuminuria, and were positively correlated with increased Ang-2. In contrast, SOD activity decreased with the degree of albuminuria and was negatively correlated with Ang-2. Multivariable linear regression analysis revealed that serum Ang-2 level was independently associated with serum levels of TNF-α (P<0.001), 8-OHdG (P=0.001), and IL-18 (P=0.003). Urinary Ang-2 level was independently associated with urinary TNF-α (P<0.001) and 8-OHdG (P=0.004) levels. Conclusion: TNF-α and 8-OHdG are associated with elevated urinary Angiopoietin-2 levels in type 2 diabetic patients with albuminuria.

Evaluation of angiopoietin 1 and 2, vascular endothelial growth factor, and tumor necrosis factor alpha levels in asthmatic children.

Asthma is characterized by chronic airway inflammation that is associated with structural changes termed airway remodeling. Recently, cytokines/mediators that augment inflammation have been attracting attention in this field. The aim of this study was to evaluate serum angiopoietin (Ang)-1, Ang-2, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF) alpha values, which have important roles in inflammation, angiogenesis, and remodeling in asthmatic children. We also documented correlations between demographic features, duration of asthma, and pulmonary function test (PFT) parameters. Randomly selected 40 children (20 male and 20 female children, aged 6-16 years) with mild or moderate persistent asthma and 32 healthy children (15 male and 17 female children, aged 6-16 years) enrolled in the study. All asthmatic children had been using inhaled corticosteroids at least for the last 3 months. Serum Ang-1 levels were significantly lower in asthmatic children than those in normal controls. The Ang-1/Ang-2 ratio was also significantly lower in asthmatic children compared with those in normal controls (p < 0.01). However, serum Ang-2, VEGF, and TNF-alpha levels were similar in the two groups. A significant positive correlation was found between VEGF and duration of asthma. No correlation between serum Ang-1, Ang-2, VEGF values, and PFT parameters was obtained. On the other hand, significant negative correlation was detected between serum TNF-alpha and forced expiratory volume in 1 second. We have shown that serum Ang-1 levels and Ang-1/Ang-2 ratio were significantly reduced and balance was toward Ang-2 in asthmatics children. This process may lead to inflammation, destabilization of blood vessels, and trigger remodeling.

Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis

Angiopoietin-2 (Ang-2) is involved in angiogenesis in both solid and hematological malignancies. In Multiple Myeloma (MM), serum Ang-2 correlates with disease progression and response to therapy. To address the patho-physiologic role of Ang-2 in MM associated angiogenesis, we used sera from patients with active MM, which contained significantly higher levels of the molecule, compared to those from patients with smoldering MM and Monoclonal Gammopathy of Undetermined Significance. MM Bone Marrow (BM) sera with high Ang-2 concentration specifically contributed to endothelial cell (EC) activation, while Ang-1 containing sera maintained EC stabilization. The functional dichotomy of Ang-1 and Ang-2 was confirmed by the triggering of distinctive signaling pathways down-stream the common Tie-2 receptor, i.e., the Akt or the ERK- phosphorylation pathway. Notably, Ang-2 but not VEGF serum levels correlated with BM micro-vessel density, further underscoring the key role of Ang-2 in angiogenesis. Western Blot, RT-PCR and immunocytochemistry identified MMEC as the major source of Ang-2, at variance with MM cells and CD14+ BM monocytes. These data suggest that Ang-2 produced in the BM milieu may contribute to MM angiogenesis and suggest that the molecule can be further exploited both as angiogenesis biomarker and as a potential therapeutic target.

Serum angiopoietin-2 and soluble VEGFR-2 levels predict malignancy of ovarian neoplasm and poor prognosis in epithelial ovarian cancer.

BackgroundThe aim of the study was to explore the serum levels of eight angiogenesis biomarkers in patients with benign, borderline or malignant epithelial ovarian neoplasms and to compare them to those of healthy controls. In addition, we aimed to study how those biomarkers predict the clinical course and survival of patients with epithelial ovarian cancer.MethodsWe enrolled 132 patients with ovarian neoplasms and 32 unaffected women in this study. Serum samples were collected preoperatively at the time of diagnosis and the levels of angiogenesis biomarkers were measured with an ELISA.ResultsLevels of Ang-1, Ang-2, VEGF, VEGF-D, VEGF/sVEGFR-2 and Ang-2/ sVEGFR-2 ratios were elevated whereas sVEGFR-2 was lower in patients with ovarian carcinoma than in women with normal ovaries, benign and/or borderline ovarian neoplasms. In ROC analysis, the area under the curve for serum Ang-2/sVEGFR-2 ratio (0.76) was greater than Ang-2 (0.75) and VEGF (0.65) but lower than for CA 125 (0.90) to differentiate ovarian cancer from benign or borderline ovarian tumors. In ovarian cancer high Ang-2/sVEGFR-2 ratio was associated with the presence of ascites, high stage and grade of ovarian cancer, with the size of primary residual tumor >1 cm and with recurrence of disease. Elevated Ang-2, VEGF, VEGF/sVEGFR-2, Ang-2/VEGF and Ang-2/sVEGFR-2 ratios and low level of sVEGFR-2 were significant predictors of poor overall survival (OS) and recurrence free survival (RFS) in univariate survival analyses.ConclusionsOvarian cancer patients had elevated levels of angiogenesis related growth factors in circulation reflecting increased angiogenesis and poor prognosis. The serum level of Ang-2 predicted most accurately poor OS and Ang-2/sVEGFR-2 ratio malignancy of ovarian neoplasms and short RFS.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-696) contains supplementary material, which is available to authorized users.