Soluble Receptors sVEGFR-1 Research Articles

Diminished Circulating Levels of Angiogenic Factors and Rage Ligands in Helminth-Diabetes Comorbidity and Reversal Following Anthelmintic Treatment.

Various epidemiological and experimental studies propose that helminths could play a preventive role against the progression of type 2 diabetes mellitus (T2DM). T2DM induces microvascular and large vessel complications mediated by elevated levels of angiogenic factors and soluble receptor for advanced glycation end product (RAGE) ligands. However, the interactions between helminths and host angiogenic factors and RAGE ligands are unexplored. To assess the relationship between a soil-transmitted helminth, Strongyloides stercoralis (Ss), and T2DM, we measured plasma levels of vascular endothelial growth factor (VEGF)-A, -C, and -D; angiopoietins 1 and 2 (Ang-1 and Ang-2); and their receptors VEGF-R1, -R2, and -R3 as well as soluble RAGE (sRAGE) and their ligands advanced glycation end products (AGEs), S100A12, and high mobility group box 1 (HMGB-1) in individuals with T2DM with or those without Ss infection. In Ss-infected individuals, we also measured the levels of aforementioned factors 6 months following anthelmintic therapy. Ss-infected individuals exhibited significantly decreased levels of VEGF-A, VEGF-C, VEGF-D, Ang-1, and Ang-2 and their soluble receptors VEGF-R1, -R2, and -R3, that increased following anthelmintic therapy. Likewise, Ss-infected individuals exhibited significantly decreased levels of AGEs and their ligands sRAGE, S100A12, and HMGB-1, which reversed following anthelmintic therapy. Our data suggest that Ss infection could play a beneficial role by limiting or delaying T2DM-related vascular complications.

Angiogenic parameters and the risk factors for thrombosis in polycythemia vera

Aim: The assessment of angiogenic parameters in so-called “liquid tumors”, such as myeloproliferative neoplasms, remains an open clinical issue. The aim of the study is to evaluate the concentration of vascular endothelial growth factor (VEGF-A) and soluble receptors sVEGFR-1 and sVEGFR-2 in relations to risk factors of thrombosis in patients with polycythemia vera (PV). Material/Methods: A total of 45 patients suffering from newly diagnosed PV and 30 healthy volunteers were enrolled into the study. Polycythemia vera was diagnosed according to the WHO (2008) criteria. In the citrated plasma samples VEGF-A, sVEGFR-1 and sVEGFR-2 were measured using ELISA tests. Results: VEGF-A concentration was three-fold higher and sVEGFR-2 significantly lower in PV patients as compared to the control group. VEGF-A concentration was significantly higher in PV patients with JAK2V617F mutation, as compared to patients without this mutation. SVEGFR-1 and sVEGFR-2 concentrations were similar in the analyzed subgroups. In PV patients with an increased number of white blood cells (WBCs), the above upper reference value (≥10 G/l), VEGF-A concentration was two-fold higher than in patients with WBCs number <10 G/l. However, sVEGFR-1 and sVEGFR-2 concentrations did not differ between the analyzed subgroups. Analysis of correlations revealed only one relation between VEGF-A and WBCs number. Conclusions: Increased VEGF-A and decreased sVEGFR-2 concentrations in polycythemia vera patients as compared to the control group indicate an intensification of the process of angiogenesis. A higher concentration of VEGF-A in PV patients with leukocytosis and a positive correlation between WBCs number and VEGF-A reflect the potential role of VEGF-A in the pathogenesis of thrombotic complications in hypercoagulable state in PV patients.

Assessment of serum levels of angiogenic factors in dizygotic twin infants with and without retinopathy of prematurity

The aim of the study was to evaluate the plasma concentrations of vascular endothelial growth factor (VEGF-A), its soluble receptors VEGFR-1 and VEGFR-2, insulin like growth factor (IGF-1) and soluble Tie-2 in twin infants with and without retinopathy of prematurity (ROP). Eleven pairs of twin infants (total 22 infants) were included in the study: There were 11 infants with advanced stage ROP in the study group and 11 infants with no ROP in the control group. Before time-point measurements, the peripheral venous blood samples were first centrifuged, and the plasma was then stored at -70°C. The plasma concentrations of the angiogenic factors were measured by using high sensitivity enzyme-linked immunosorbent assay (ELISA) kits. The average gestational age of the infants at the time of birth and the time at which the serum samples were collected were 30.5±2.3 and 37.5±2.5 weeks, respectively. The average serum levels of all the angiogenic factors were higher in infants with ROP, but the differences were not statistically significant (p>0.05). In this study, serum samples of twins with and without ROP were evaluated simultaneously. The time of serum sampling in the study group corresponded to the period of phase 2 ROP. Therefore, there appeared to be no difference between the ROP group and the control group. J. Exp. Clin. Med., 2013; 30:39-43

In Vitro Expression of Vascular Endothelial Growth Factor and Its Receptors by Placental Macrophages

The expression of VEGF and membrane-bound and soluble forms of the VEGF-R1 receptor in cultured placental macrophages (trimesters I and III of pregnancy) was studied by flow cytometry, cytometric bead array, and ELISA. Nearly all population of placental macrophages (98%) was capable of producing VEGF during the early and late gestational periods. However, the expression of cellular VEGF-R1 varied from 3.4 to 92%. VEGF secretion was relatively low in the first and third trimesters (0.5 and 1.1 pg/10(5) cells, respectively). Cultured placental macrophages produced soluble receptor sVEGF-R1 in the first and third trimesters (86.4 and 36.4 pg/10(5) cells, respectively). Stimulation with LPS was followed by a 4-fold increase in sVEGF-R1 secretion. Our results indicate that placental macrophages are involved in the autocrine and paracrine regulation in chorionic villi. The data suggest that these cells have a physiological and pathogenetic role in gestation.

PaFLO: Pazopanib with 5-fluorouracil, leucovorin, and oxaliplatin (FLO) as first-line treatment in advanced gastric cancer: A randomized phase II study of the Arbeitsgemeinschaft internistische Onkologie (AIO).

TPS4138 Background: VEGF inhibition in gastric cancer shows promising improvement of remission rate and progression-free survival (Ohtsu et al., JCO 2011). Pazopanib is an orally available tyrosine kinase inhibitor (TKI) selectively inhibiting VEGFR-1, -2, -3, c-kit and PDGFR. It is approved for treating renal cell cancer. A phase-I trial showed good tolerability of pazopanib with full-dose FOLFOX in solid tumors (Brady et al., ASCO, 2009). FLO is a widely used combination for advanced gastric cancer recommended in national guidelines. Methods: 75 Patients with HER-2-negative locally advanced or metastatic adenocarcinoma of the stomach or the gastro-esophageal junction will be randomized in a 2:1 ratio to A: FLO (F 2600mg/m2 as 24h infusion, L 200mg/m2, O 85 mg/m2) d1 + pazopanib (800mg) d1-14 and B: FLO; repeated for 12 2-week cycles, followed by a maintenance therapy with pazopanib alone in A and an observation period in B until disease progression. Primary endpoint is progression-free survival rate (PFSR) at 6 months, secondary endpoints are PFSR at 9 and 12 months, median PFS, response rate, duration of response, toxicity, tolerability and overall survival. Additionally, we evaluate the predictive and prognostic relevance of PIGF, VEGF, and the respective soluble receptors sVEGFR1 and sVEGFR2 as biomarkers for clinicopathological parameters, clinical response to treatment and tumor volume change. Based on a phase-III trial demonstrating a 6-month PFSR of 44% with FLO (Al-Batran et al., 2008), we estimate a 6-month PFSR of 55% in the experimental group. Given an alpha error of 0.1 and a beta error of 0.2 in a Simon 2-stage minimax design, in the first stage ≥12 of 30 patients need to be progression free at 6 months to continue and after the second stage ≥25 of 50 patients should be progression free at 6 months to justify further evaluation. Randomization is performed to estimate selection bias according to pazopanib-specific exclusion criteria for comparison with historical data. Study protocol received ethics committee approval in November 2011 and is currently recruiting patients in 15 AIO centers.

Soluble VEGF receptor 1 promotes endothelial injury in children and adolescents with lupus nephritis

Endothelial cell injury plays a key role in the pathogenesis of lupus nephritis (LN) and atherosclerosis. The aim of this study was to identify factors involved in the process of endothelial damage in children and adolescents with LN. We evaluated the relationship between plasma vascular endothelial growth factor (VEGF), its soluble receptors sVEGFR-1 and sVEGFR-2 and markers of endothelial inflammation and injury (angiopoietin-2 and thrombomodulin, respectively) in 23 children and adolescents with LN (active LN, n = 14; inactive LN, n = 9; mean age 15 years) and 20 healthy controls (HC; mean age 12 years). VEGF, sVEGFR-1, angiopoietin-2 and thrombomodulin levels were significantly higher in children and adolescents with active LN than in patients in remission or HC. In active LN, however, VEGF was inversely related to sVEGFR-1 (r = -0.802, p < 0.001), angiopoietin-2 (r = -0.684, p = 0.007) and thrombomodulin (r = -0.697, p = 0.006). There was a significant positive correlation between sVEGFR-1 and thrombomodulin (r = 0.814, p < 0.0001), but sVEGFR-2 did not significantly differ between the patient groups and did not correlate with thrombomodulin (r = 0.046, p = 0.833). sVEGFR-1 may play an important role in promoting endothelial damage in children and adolescents with active LN and could possibly be used to monitor disease severity.

Serum levels of vascular endothelial growth factor and its receptors in patients with severe autism

Objective: To study vascular endothelial growth factor (VEGF) and its soluble receptors sVEGFR-1 and -2 in autism. Design and methods: We measured serum levels of angiogenic molecules in 22 patients with severe autism and 28 controls. Results: Patients and controls had similar sVEGFR-2 levels, but VEGF levels were lower and sVEGFR-1 higher in patients with autism. Conclusion: The imbalance between VEGF and its receptor sVEGFR-1 may be involved in the pathophysiology of autism.

Comparison of serum VEGF and its soluble receptor sVEGFR1 with serum cell-free DNA in patients with breast tumor

Background: The observed elevated levels of vascular endothelial growth factor (VEGF), its soluble receptor (sVEGFR1) and cell-free DNA (cfDNA) in the serum of patients with various cancers have attracted much attention to the possibility of using these agents as biomarkers for cancers. We wanted to find out whether VEGF, VEGFR1 or cfDNA is a biomarker for breast cancer. Methods: In this study, we used enzyme-linked immunosorbent assay (ELISA) to examine the levels of serum VEGF and VEGFR1 in 23 patients with benign tumors, 19 patients with breast cancer and 32 age-matched healthy females. The levels of circulating cell-free DNA were measured using TaqMan real-time PCR analysis for the glyceraldehydes 3 phosphate dehydrogenase gene (GAPDH), We compared the serum levels of VEGF and its soluble receptors with those of the cell-free serum DNA. Results: In terms of serum levels of either VEGF or its soluble receptors VEGFR1, we found no significant difference between healthy individuals and women with benign breast tumors and breast cancer. However, there was a significant increase in circulating cell-free DNA in women with both benign and malignant breast tumors when compared with the corresponding healthy control group. We also found a significant negative correlation between VEGF and its soluble receptor VEGFR1 ( r = −0.328 and p = 0.004), and a significant positive correlation between VEGF and cell-free serum DNA ( r = 0.241 and p = 0.033). Conclusions: We can conclude that quantitative analysis of circulating cell-free DNA in serum may provide molecular biological understanding of breast tumors in women. It would also suggest that serum levels of VEGF and VEGFR1 have less significance.

VEGF-A, VEGFR-1, VEGFR-2 and Tie2 levels in plasma of premature infants: relationship to retinopathy of prematurity

Aim:To study prospectively the plasma levels of vascular endothelial growth factor (VEGF-A), its soluble receptors sVEGFR-1, sVEGFR-2 and soluble Tie2 in premature infants. To identify their changes related to the...

Serum markers of angiogenesis in patients with von Hippel-Lindau Disease

1033 Background: Von Hippel-Lindau disease is an autosomal dominant genetic cancer predisposition syndrome characterized by hemangioblastomas of the retina and cerebellum, renal cell carcinoma, and other tumors. The disease results from a mutation in the 3p25–26 region and this gene conforms to Knudson's two-hit hypothesis of carcinogenesis. The protein product of the VHL gene participates in ubiquitin-mediated proteolysis of hypoxia inducible factors 1 and 2, which upregulate the expression of a variety of proteins. Mutations in the VHL gene lead to decreased proteolysis of HIF, in turn leading to upregulation of downstream products, including VEGF. The tumors associated with this syndrome are often not detected until the second decade of life or later; by this time, damage to organs has already occurred and the only treatment available is surgical. The development of pre-clinical serum markers would be of important clinical utility in detecting at-risk individuals. Methods: This study examines the use of the angiogenic factor VEGF and its soluble receptor sVEGFR1 as serum markers in Von Hippel-Lindau disease in patients with mutations of the VHL gene with varying levels of active disease, compared with the same number of mutation negative family controls. Results: In our preliminary analysis, data has been collected from a total of 27 subjects. 18 (66.7%) of them are affected with VHL, 9 (33.3%) non-affected. The mean concentration of VEGF is 213.7 (SD 148.1) pg/ml in VHL affected subjects, and 88.3 (SD 87.4) pg/ml in non-affected subjects. The difference in VEGF levels in mutation positive and mutation negative individuals was highly significant (p=0.008) A trend was observed towards increasing VEGF levels and number of disease sites involved. Levels of sVEGFR1 did not differ between the two groups. Conclusion: The results suggest preliminarily that subjects affected with VHL disease have significantly higher concentrations of VEGF, as compared to those non-affected with VHL disease (Mean of 213.7 +/− 148.1 vs. 88.3 +/− 87.4; p = 0.008). No significant financial relationships to disclose.

Serum markers of angiogenesis in patients with von Hippel-Lindau Disease

1033 Background: Von Hippel-Lindau disease is an autosomal dominant genetic cancer predisposition syndrome characterized by hemangioblastomas of the retina and cerebellum, renal cell carcinoma, and other tumors. The disease results from a mutation in the 3p25–26 region and this gene conforms to Knudson's two-hit hypothesis of carcinogenesis. The protein product of the VHL gene participates in ubiquitin-mediated proteolysis of hypoxia inducible factors 1 and 2, which upregulate the expression of a variety of proteins. Mutations in the VHL gene lead to decreased proteolysis of HIF, in turn leading to upregulation of downstream products, including VEGF. The tumors associated with this syndrome are often not detected until the second decade of life or later; by this time, damage to organs has already occurred and the only treatment available is surgical. The development of pre-clinical serum markers would be of important clinical utility in detecting at-risk individuals. Methods: This study examines the use of the angiogenic factor VEGF and its soluble receptor sVEGFR1 as serum markers in Von Hippel-Lindau disease in patients with mutations of the VHL gene with varying levels of active disease, compared with the same number of mutation negative family controls. Results: In our preliminary analysis, data has been collected from a total of 27 subjects. 18 (66.7%) of them are affected with VHL, 9 (33.3%) non-affected. The mean concentration of VEGF is 213.7 (SD 148.1) pg/ml in VHL affected subjects, and 88.3 (SD 87.4) pg/ml in non-affected subjects. The difference in VEGF levels in mutation positive and mutation negative individuals was highly significant (p=0.008) A trend was observed towards increasing VEGF levels and number of disease sites involved. Levels of sVEGFR1 did not differ between the two groups. Conclusion: The results suggest preliminarily that subjects affected with VHL disease have significantly higher concentrations of VEGF, as compared to those non-affected with VHL disease (Mean of 213.7 +/− 148.1 vs. 88.3 +/− 87.4; p = 0.008). No significant financial relationships to disclose.

Vascular endothelial growth factor and its soluble receptors VEGFR-1 and VEGFR-2 in the serum of patients with systemic lupus erythematosus.

We investigated the serum concentration of vascular endothelial growth factor (VEGF) and its two soluble receptors, sVEGFR-1 and sVEGFR-2, in a group of 60 patients with systemic lupus erythematosus (SLE), and 20 healthy controls, using an enzyme-linked immunosorbent assay. We examined a possible association between serum levels of these proteins and certain clinical and laboratory parameters as well as SLE activity. VEGF, sVEGFR-1 and sVEGFR-2 were detectable in all patients with SLE and in all normal individuals. The VEGF level was higher in active SLE (mean, 300.8 pg/ml) than in inactive SLE (mean, 165.9 pg/ml) (p < 0.05) or in the control group (mean, 124.7 pg/ml) (p < 0.04). The highest sVEGFR-1 concentrations were also detected in active SLE patients (mean, 42.2 pg/ml) and the lowest in inactive disease (mean, 32.0 pg/ml) (p < 0.01). In contrast, the levels of sVEGFR-2 were lower in SLE (mean, 12557.6 pg/ml) than in the control group (mean, 15025.3 pg/ml) (p < 0.05). We found a positive correlation between sVEGFR-1 concentration and the SLE activity score p = 0.375 (p < 0.004) and a negative, but statistically insignificant correlation between sVEGFR-2 and SLE activity (p = -0.190, p > 0.05). Treatment with steroids and cytotoxic agents did not influence VEGF or its soluble receptors levels. In conclusion, in SLE patients the levels of VEGF and sVEGFR-1 are higher in patients with active SLE than in inactive disease or healthy persons. In contrast, the level of sVEGFR-2 is lower in active SLE than in inactive disease. The imbalance between VEGF and its soluble receptors may be important in SLE pathogenesis.