Low Vascular Endothelial Growth Factor Research Articles

Identifying the association of contrast enhancement with vascular endothelia growth factor expression in anaplastic gliomas: a volumetric magnetic resonance imaging analysis.

Contrast enhancement is a crucial radiologic feature of malignant brain tumors, which are associated with genetic changes of the tumor. The purpose of the current study was to investigate the potential relationship among tumor contrast enhancement with MR imaging, vascular endothelial growth factor (VEGF) expression, and survival outcome in anaplastic gliomas. MR images from 240 patients with histologically confirmed anaplastic gliomas were retrospectively analyzed. The volumes of T2 hyperintense, contrast enhanced regions and necrotic regions on postcontrast T1-weighted images were measured. The ratio of the enhanced volume to necrotic volume was compared between patients with high versus low levels of VEGF expression and was further used in the survival analysis. The volumetric ratio of enhancement to necrosis was significantly higher in patients with low VEGF expression than in those with high VEGF expression (Mann-Whitney, p = 0.009). In addition, the enhancement/necrosis ratio was identified as a significant predictor of progression-free survival (Cox regression model, p = 0.004) and overall survival (Cox regression model, p = 0.006) in the multivariate analysis. These results suggest that the volumetric ratio of enhancement to necrosis could serve as a noninvasive radiographic marker associated with VEGF expression and that this ratio is an independent predictor for progression-free survival and overall survival in patients with anaplastic gliomas.

Lactotrophs: the new and major source for VEGF secretion and the influence of ECM on rat pituitary function in vitro.

Vascular endothelial growth factor (VEGF) plays a pivotal role in pituitary endocrine function by influencing fenestration and blood vessel growth. Folliculostellate (FS) cells, which represent only a small number of pituitary cells, are recognized to produce VEGF. Tissue sections and primary pituitary cell cultures from rat pituitary glands were performed to co-localize VEGF and pituitary lactotrophs, which represents nearly 50% of all pituitary cells, by immunofluorescence. VEGF is co-localized with prolactin-producing cells in vivo and in vitro. FS cells are present infrequently in vivo (1.6%) and in vitro (2.4%). Culture supernatants were analyzed for the presence of VEGF by ELISA. VEGF levels are always significantly lower in supernatants from the cells that are seeded on Matrigel extracellular matrix (ECM) compared to the cells grown on plastic. Lower VEGF concentrations in supernatants from the pituitary cells cultured on ECM may reflect a more adequate cell environment compared to culture on plastic. These results demonstrate for the first time, that VEGF is expressed by lactotrophs, which outnumber FS cells. These results are of potential clinical relevance especially in oncology for the interpretation of studies investigating anti-angiogenic treatment of pituitary tumors.

Endothelial repairing function in patients with symptomatic middle cerebral arterial stenosis after stent implantation

Objective To investigate the relation between endothelial repairing function and in-stent restenosis in patients with symptomatic middle cerebral arterial (MCA) stenosis after stent implantation. Method Sixty-six patients with symptomatic MCA stenosis underwent percutaneous stent implantation. Cranial CTA revealed that 23 patients had MCA restenosis (restenosis group) 1 year after stenting, including 14 cases with >50% stenosis and 1 case with MCA occlusion, and 43 patients had no restenosis (non-restenosis group). The number of endothelial progenitor cells (EPC) was examined by flow cytometry, the adhesion function of EPC was tested by adhesion assay, the migration ability of EPC was tested by Transwell method and serum vascular endothelial growth factor(VEGF) levels were measured by ELISA. The relationship of endothelial repairing function with restenosis was analyzed. Results The MCA stent implantations were successfully performed in all patients. The EPC number (33.7±4.6 vs. 61.6± 6.4), adhesion activities (26.1±7.5 vs. 56.3±9.6), migration activities (12.0±3.9 vs. 21.4±6.5) and serum VEGF level [(56.7±14.6) vs. (89.6±17.32) ng/L] in restenosis group were significantly lower than those in non-restenosis group (t=18.48, 13.09, 6.34 and 7.73, all P<0.05). Conclusion For patients with MCA stenosis after percutaneous stent implantation the increased risk of in-stent restenosis is associated with low level of EPCs and their migration ability, and low serum VEGF level. Key words: Middle cerebral artery; Stent; Stem cells, endothelial cells; Vascular endothelial growth factors; Constriction, pathologic

Plasma Vascular Endothelial Growth Factor (VEGF) Levels Correlate with Thrombocytopenia of Various Etiology

The mechanisms leading to thrombocytopenia include (1) decreased platelet production; (2) splenic sequestration due to splenomegaly; and (3) increased peripheral consumption and/or destruction. VEGF, physiologically secreted by endothelial cells, is also produced in the alpha-granules of platelets. VEGF measured in plasma will presumably reflect its level in in vivo circulation, released from both endothelial cells and platelets. We hypothesized that thrombocytopenic disorders characterized by increased platelet destruction would manifest with increased plasma VEGF level; whereas disorders characterized by decreased platelet production or platelet sequestration would show low or normal plasma VEGF level.Methods: This is a prospective study approved by IRB. Patients were eligible if they had platelet counts less than 150,000/ul at diagnosis. Plasma and serum specimens were collected at baseline and multiple time points towards recovery, and VEGF levels were determined using commercial ELISA kit from RayBiotech and BioRad according to manufacturer’s instructions. We enrolled 69 patients and 50 were included in the analysis. Nineteen patients were excluded from the analysis due to the following: the specimen was yielding non detectable serum VEGF value, or higher plasma VEGF level than serum level (both of above were used as internal controls for the validity of the experiment), or platelet count more than 150,000/ul. Five healthy controls were also enrolled.Results: Among the patients, the diagnoses were (A) 18 with ITP, (B) 13 with sepsis, (C) 4 with TTP, (D) 6 with MDS or AML (E) 6 with splenomegaly and (G) 3 with gestational thrombocytopenia. There was wide inter-patient variation in each group. The inter-experiment variation on the same specimen was less than 30% in most of the cases. The mean plasma VEGF value in the ITP, sepsis, TTP and groups were 49.2 ± 36.1 ng/ml, 158.9± 380.5 ng/ml, 204.5±222.6 ng/ml respectively, and were statistically higher than that of the control group 9.1±18.1 ng/ml, (p= 0.032, 0.029 and 0.022 respectively, Mann-Whitney test). On the other hand, the mean plasma VEGF value in the MDS, splenomegaly and gestational thrombocytopenia groups were 29.8±49.1 ng/ml, 13.2±21.3ng/ml and 3.0±1.8 ng/ml respectively, similar to that of the control group (p> 0.05 in all three groups, Mann-Whitney test). One patient in the sepsis group showed an extremely high plasma VEGF value (1447 ng/ml).Conclusion: Plasma VEGF value is a potential biomarker which can aide in the differential diagnosis of thrombocytopenia of various etiologies. Plasma VEGF levels were increased in most patients with thrombocytopenia from ITP, sepsis and TTP, but not in patients who have thrombocytopenia from MDS, splenomegaly or gestational thrombocytopenia. The elevation of plasma VEGF in those conditions could be due to increased epithelial production or release from platelet activation or destruction, the differentiation of which will need further study. A larger scale study is warranted to confirm the above result. DisclosuresNo relevant conflicts of interest to declare.

Statins in rhegmatogenous retinal detachment are associated with low intravitreal angiopoietin-2, VEGF and MMP-2 levels, and improved visual acuity gain in vitrectomized patients.

In rhegmatogenous retinal detachment (RRD), intravitreal growth factors and cytokines may compromise post-vitrectomy outcomes. Here, we analysed perioperative intravitreal protein levels of potent vasoactive, pro-inflammatory, and extracellular matrix-remodelling factors in RRD eyes of patients treated with statins and evaluated post-vitrectomy outcome in the same study eyes. Institutional, retrospective, observational study of 14 patients operated on for RRD while on statins compared to patients without statin medication (n = 82). Vitreous samples were subjected to protein measurements of angiopoietin (ANGPT)-1 and -2, transforming growth factor-β1, and vascular endothelial growth factor (VEGF) by ELISA, and of matrix metalloproteinase (MMP)-2 and -9 by gelatin zymography. A 1-month best-corrected visual acuity (BCVA) gain was modelled by Student's T-test and multivariate linear regression with concomitant perioperative medication. Cumulative 12-month revitrectomy frequency was modelled by Kaplan-Meier log-rank test. Intravitreal levels of ANGPT-2 (49.2 ± 33.1 vs. 112.8 ± 134.1 pg/ml, mean ± SD, p < 0.001), VEGF (2.3 ± 2.4 vs. 17.7 ± 57.8 pg/ml, p = 0.021), and MMP-2 (1107.1 ± 884.6 vs 1976.4 ± 970.1 AU/ml, p = 0.005) in RRD eyes of patients treated with statins were lower than in non-statin-treated controls. Patients on statins had better 1-month BCVA improvement than did those not on statins (p = 0.022), with no difference in 1-year re-vitrectomy rates. Intravitreal levels of ANGPT-2, VEGF, factors involved in vascular permeability and inflammation, and activity of MMP-2, the factor connected with breakdown of basement membrane and fibroproliferation, were lower in RRD eyes of patients with statin treatment. At 1-month, postoperative BCVA gain was improved in statin-treated RRD eyes, suggesting that statin administration may be effective in preventing inflammation-related PVR formation.

Correlation between the expression of vegf and survival in osteosarcoma

Objective: To present a series of 50 consecutive patients with non-metastatic extremity osteosarcoma, and attempt to correlate expression of the vascular endothelial growth factor (VEGF) protein in biopsy tissue to their prognosis regarding overall survival, disease-free survival and local recurrence. Methods: Fifty cases of non-metastatic osteosarcoma of the extremities treated between 1986 and 2006 at Instituto de Ortopedia e Traumatologia da Universidade de São Paulo, São Paulo, Brasil, were evaluated regarding expression of the VEGF protein. There were 19 females and 31 males. The mean age was 16 years old (range 5-28 years old) and the mean follow-up was 60.6 months (range 25-167 months). The variables studied were age, gender, anatomic location, type of surgery, surgical margins, tumor size, post chemotherapy necrosis, local recurrence, pulmonary metastasis and death. Results: Thirty-six patients showed VEGF expression on 30% or less cells (low), and the remaining 14 cases had VEGF expression above 30% (high). Among the 36 patients with low VEGF expression, nine developed pulmonary metastasis and four died (11.1%). Among the 14 patients with high VEGF expression, six developed pulmonary metastasis and three died (21.4%). Conclusion: There was no statistically significant correlation between the expression of VEGF and any of the variables studied. Level of Evidence IV, Therapeutic Study.

Inhibitory effects of maslinic acid upon human esophagus, stomach and pancreatic cancer cells

Apoptotic, anti-invasive and anti-migratory effects of maslinic acid (MA) at 4, 8, or 16 µM in human esophageal squamous cancer cell line, OE33; gastric cancer cell line, SGC-7901; and pancreatic cancer cell line, Panc-1, were examined. MA treatments inhibited OE33 and SGC-7901 cells growth at 21–66% and 32–75%, respectively; but lowered Panc-1 viability at 13–27% only. MA treatments increased cleaved caspase-3 and Bax expression, and raised caspase-3 and caspase-8 activities in OE33 and SGC-7901 cells. MA treatments also increased DNA fragmentation and decreased reactive oxygen species production in these two cell lines. MA treatments declined invasion and migration in OE33 and SGC-7901 cells, and lowered vascular endothelial growth factor and transforming growth factor-beta1 levels in these cells. MA suppressed hypoxia-inducible factor-1alpha, matrix metalloproteinase (MMP)-2 and MMP-9 expression in OE33 and SGC-7901 cells. These findings indicated that this triterpene was a potent agent against esophagus and stomach cancers.

Fatores angiogênicos e antiangiogênicos na fisiopatologia da pré-eclâmpsia e seu uso na prática obstétrica atual

Pre-eclampsia is a leading cause of maternal morbidity and mortality, perinatal death, premature birth and intrauterine growth restriction. Although most of women present a good outcome, the delay in diagnosis may contribute to the evolution to a more severe form, eclampsia. A large number of studies have been published on this subject, yet the etiology of pre-eclampsia remains unknown. The study of angiogenic factors, such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1), allows the expansion of knowledge about the pathophysiology of pre-eclampsia. Patients analyzed after diagnosis of pre-eclampsia had higher serum levels of sFlt-1 and lower PlGF and VEGF than the control group matched for gestational age. sFlt-1 acts as antagonist as it binds to angiogenic factors and prevents their interaction with cell surface receptors. These changes were more pronounced when the patient developed early pre-eclampsia (&lt; 34 weeks) or intrauterine growth restriction. These factors are already being used for prediction of the disease in the first trimester, especially the early presentations of the disease, and are promising to help in the differential diagnosis between pre-eclampsia and diseases that have similar clinical picture, such as systemic lupus erythematosus (SLE). This autoimmune disease affects mainly women of reproductive age and is associated with adverse pregnancy outcomes. Few studies have evaluated the angiogenic and antiangiogenic factors in women with SLE. Apparently, there is an increased sFlt-1 in patients with SLE and pre-eclampsia, however the results can not yet be applied in clinical practice considering the paucity of data. Prospective studies in pregnant women with SLE are being developed for the differential diagnosis of hypertensive disorders during pregnancy, and may directly influence the support provided to women with high risk pregnancy.

Maternal/newborn VEGF-C936T interaction and its influence on the risk, severity and prognosis of preeclampsia, as well as on the maternal angiogenic profile

Objective: To analyze the influence of maternal/newborn vascular endothelial growth factor (VEGF)-CT936 interaction as a modulating factor in preeclampsia as well as its influence on the maternal angiogenic balance.Methods: Seventy pairs of preeclamptic women/newborns and 94 pairs of normal pregnant mothers/newborns were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum VEGF and soluble VEGF receptor-1 (sVEGFR-1) levels were measured using ELISA.Results: The risk to develop mild (odds ratio; OR: 3.79, p = 0.008) and severe (OR: 2.94, p = 0.037) preeclampsia being increased in association with the CT936-VEGF genotype and increased in severe preeclampsia to 6.07 (p = 0.03) if the women were carriers of the homozygous TT936-VEGF genotype. The presence of the VEGF-T936 allele in both the mother and the newborn significantly increases the risk of pregnancy-induced hypertension (PIH), mild and severe preeclampsia. If both the mothers and newborns were carriers of the VEGF-T936 allele, significantly lower VEGF and higher sVEGFR-1 levels were observed for all types of preeclampsia. Pregnant women with PIH and severe preeclampsia delivered at a significantly earlier gestational age neonates with a significantly lower birth weight if both the preeclamptic mothers and their newborns were carriers of the VEGF-T936 allele.Conclusions: Our study suggests the role of maternal/fetal VEGF-CT936 polymorphism as a modulating factor in preeclampsia, which affects the angiogenic balance in preeclamptic mothers, as well as their pregnancy outcome.

Vascular Endothelial Growth Factor and its Soluble Receptor-1 as Surrogate Markers for Subjects with High-risk of Cardiovascular Disease

Background: Vascular endothelial growth factor (VEGF) and its soluble receptor-1 (sVEGFR-1) can either act benefi cially or adversely on cardiovascular health depending on the context. An understanding of VEGF regulation in subclinical atherosclerosis would help to identify individuals who may need more intensive efforts in risk modifi cation as preventive measures. Subjects and Methods: The population in this study consisted of subjects without any modifi able risks and hypercholesterolemic subjects with low or high cardiovascular disease (CVD) risks. A total of 227 subjects were recruited from employees of the Electricity Generating Authority of Thailand and their cardiovascular risk factor history as well as clinical and laboratory data were collected. Plasma VEGF and sVEGFR-1 were measured using enzyme-linked immunosorbent assay. Results: Biphasic association between the sVEGFR-1-to-VEGF (R/V) ratio and the VEGF concentration indicated VEGF upregulation at concentrations above 12.99 pg/mL and VEGF entrapment at a concentration below this level. Rates of VEGF upregulation in low- and high-risk groups were respectively found to be 2.6-fold (P = 0.01) and 4.6-fold (P = 0.03) above the zero risk group. The R/V ratio, which is positively correlated to cholesterol level (P 3.4, high-risk subjects compared to low-risk subjects had greater odds of being observed with severe risk scores (odds ratio = 8.2, P Conclusion: VEGF upregulation in subjects with CVD risks is correctively controlled within the physiologic boundary and represents an attempt at vascular repair. Low VEGF levels and high R/V ratios in high-risk subjects are warning signs with respect to cardiovascular health and may indicate the need for more aggressive risk factor treatment in order to prevent the occurrence of undesirable cardiovascular events. Key words: Cardiovascular disease risk factor, the Electricity Generating Authority of Thailand risk score, hypercholesterolemia, soluble vascular endothelial growth factor receptor-1-to-vascular endothelial growth factor ratio, vascular endothelial growth factor protective function.

Plasma Vascular Endothelial Growth Factor (VEGF) Predicts Vascular Invasion in Patients with Hepatocellular Carcinoma (HCC) Undergoing Liver Transplantation.

Background Tumor vascular invasion is the most important feature associated with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Studies demonstrated the prognostic value of circulating vascular endothelial growth factor (VEGF) levels in patients undergoing liver resection or locoregional therapies (LRT) for HCC. This study evaluates the correlation between plasma VEGF level and clinicopathological variables in patients with HCC undergoing LT in a large western transplant center. Methods We retrospectively analyzed 164 patients with HCC undergoing LT. Pre-LT plasma VEGF levels were measured by enzyme-linked immunosorbent assay. Pre-LT Plasma VEGF cut-off value determined by receiver operating characteristics (ROC) curve analysis was set to correlate with clinicopathological variables and tumor recurrence. Results Pre-LT plasma VEGF levels ranged from 30 to 272 pg/ml (median 31). ROC analysis indicated the cut-off value with best sensitivity and specificity for predicting vascular invasion was 45pg/ml for VEGF. The sensitivity and specificity for VEGF was 59.6% and 77.8%. VEGF revealed a larger area under the ROC curve than AFP (0.693 vs 0.614). Pre-LT plasma VEGF level >45pg/ml was significantly associated with AFP >200ng/ml (P=0.0281), pre-LT LRT (p=0.033), multiple tumors (p=0.045), total tumor diameter ≥5 cm (p=0.022), tumor vascular invasion (p=0.000), and HCC beyond Milan criteria (p=0.017). On multivariate analysis, plasma VEGF >45 pg/ml was an independent preoperative predictor of tumor vascular invasion (odds ratio 5.021, 95% confidence interval 1.997-12.627, p=0.001). Twenty patients (37.0%) in the high plasma VEGF level group and 8 patients (7.3%) in the low plasma VEGF level group developed HCC recurrence (p=0.000). Conclusion In patients with chronic end stage liver disease undergoing LT with HCC, pre-LT plasma VEGF level >45 pg/ml may be an independent predictor of tumor vascular invasion.

Laminin promotes vascular network formation in 3D in vitro collagen scaffolds by regulating VEGF uptake

Angiogenesis is an essential neovascularisation process, which if recapitulated in 3D in vitro, will provide better understanding of endothelial cell (EC) behaviour. Various cell types and growth factors are involved, with vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 key components. We were able to control the aggregation pattern of ECs in 3D collagen hydrogels, by varying the matrix composition and/or having a source of cells signalling angiogenic proteins. These aggregation patterns reflect the different developmental pathways that ECs take to form different sized tubular structures. Cultures with added laminin and thus increased expression of α6 integrin showed a significant increase (p<0.05) in VEGFR2 positive ECs and increased VEGF uptake. This resulted in the end-to-end network aggregation of ECs. In cultures without laminin and therefore low α6 integrin expression, VEGFR2 levels and VEGF uptake were significantly lower (p<0.05). These ECs formed contiguous sheets, analogous to the ‘wrapping’ pathway in development. We have identified a key linkage between integrin expression on ECs and their uptake of VEGF, regulated by VEGFR2, resulting in different aggregation patterns in 3D.

Correlation between ¹⁸F-fluoromisonidazole PET and expression of HIF-1α and VEGF in newly diagnosed and recurrent malignant gliomas.

Hypoxia and its consequences at the molecular level promote tumour progression and affect patient prognosis. One of the main early cellular events evoked by hypoxia is induction of hypoxia-inducible factor 1 (HIF-1) and subsequent upregulation of vascular endothelial growth factor (VEGF). In this study we sought to determine whether hypoxia detected by (18)F-fluoromisonidazole (FMISO) PET accurately reflects the expression of HIF-1α and VEGF in the tumour and can be used as a biomarker of antiangiogenic treatment and as a prognostic factor in newly diagnosed and recurrent malignant gliomas. Enrolled in this study were 32 patients with newly diagnosed glioma and 16 with recurrent glioma of grade III or grade IV. All the patients had undergone FMISO PET preoperatively. The maximum tumour-to-blood FMISO activity ratio (T/Bmax) was used to evaluate the degree of tumour hypoxia and the hypoxic volume (HV) was calculated using a tumour-to-blood FMISO uptake ratio of ≥1.2. Immunohistochemical expressions of HIF-1α and VEGF were evaluated semiquantitatively using the immunoreactivity score (IRS, scores 0 to 12) and the correlation was examined between IRS of HIF-1α or VEGF and FMISO uptake of the tumour (SUVtumour) using navigation-based sampling. Survival was estimated using the Kaplan-Meier method in relation to the T/Bmax and the HV. The T/Bmax and the HV in grade IV gliomas were significantly higher than in grade III gliomas (P < 0.01 and P < 0.01, respectively). Moderate to strong HIF-1α and VEGF expression was observed in the majority of malignant gliomas. The IRS of HIF-1α and VEGF in the tumour were not significantly different between grade III and grade IV gliomas. The IRS of HIF-1α in the tumour did not correlate with the SUVtumour of FMISO in either newly diagnosed or recurrent glioma. There was a significant but weak correlation between the IRS of VEGF and the SUVtumour of FMISO in newly diagnosed glioma, but not in recurrent glioma. The overall survival time in patients with a small HV and a low FMISO T/Bmax was significantly longer than in those with a large HV and a high FMISO T/Bmax (P < 0.01 and P < 0.05, respectively). Preoperative FMISO uptake is significantly correlated with the expression of VEGF in the tumour and might be used as a biomarker of antiangiogenic treatment in newly diagnosed malignant gliomas. However, caution is required because the correlation was weak and there was a large overlap of FMISO uptake between glioma with high and low VEGF expression. In addition, hypoxia determined by FMISO PET appears to be a suitable biomarker for predicting a highly malignant tumour and a poor prognosis in patients with malignant glioma.

The Effects of Infliximab or Adalimumab on Vascular Endothelial Growth Factor and Angiopoietin 1 Angiogenic Factor Levels in Inflammatory Bowel Disease

Infliximab and adalimumab effectiveness might be related with changes in angiogenic factors. The aim of the study was to compare the concentrations of angiogenic proteins in patients with inflammatory bowel disease (IBD) and healthy controls and to analyze changes in the levels during infliximab and adalimumab treatment. A prospective case-control study was conducted in 37 patients with IBD starting treatment with infliximab (16 with Crohn's disease and 6 with ulcerative colitis) or adalimumab (15 with Crohn's disease) and 40 control subjects. Four samples were taken from IBD patients, one before each of the first 3 doses of infliximab/adalimumab and one at week 14. Serum levels of vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 1 (Ang1), angiopoietin 2, and Tie2 were measured using enzyme-linked immunosorbent assay. Patients with IBD had higher VEGF levels than control subjects (511.5 ± 255.6 versus 395.5 ± 256.4; P = 0.05). Patients who achieved remission at the third dose of anti-TNF-alpha had lower VEGF levels at baseline (453.5 ± 250.7 versus 667.5 ± 153.9 pg/mL) and before the second (409.7 ± 217 versus 681.3 ± 350.6 pg/mL) and third (400.5 ± 222.8 versus 630.4 ± 243.1 pg/mL) doses compared with those with no remission (P < 0.05). Ang1 levels decreased before each treatment dose in patients who achieved remission (P < 0.05). High baseline VEGF levels predicted for a poor response to anti-TNF-alpha therapy (area under the receiver operating characteristics curve = 0.8), whereas high Ang1 levels were associated with disease remission (area under the receiver operating characteristics curve = 0.7). Concentrations of angiogenic proteins did not correlate with clinical activity scores. Circulating VEGF and Ang1 levels decrease after anti-TNF-alpha therapy and may predict response to treatment. Whether these changes are a direct effect of anti-TNF-alpha therapy or a sign of disease improvement remains to be elucidated.

Relationship between vascular endothelial growth factor and left ventricular dimension in patients with acute myocardial infarction

BackgroundAlthough vascular endothelial growth factor (VEGF) is elevated in patients with acute myocardial infarction (AMI), the clinical significance of its elevation remains unclear. The present study was designed to determine the relationship between VEGF and left ventricular dimension in patients with AMI. Methods and resultsPlasma VEGF levels were examined by enzyme-linked immunosorbent assay daily for one week and then weekly for four weeks in 38 patients with AMI (65.4±1.7 years). Left ventriculography was performed at 14 days, 6 months, and 2 years after the onset of AMI. Plasma VEGF levels were significantly elevated and reached a peak on day 6. Peak plasma VEGF levels positively correlated with both end-diastolic and end-systolic volume indices at 14 days after the onset of AMI. When patients with AMI were divided into two groups according to plasma VEGF levels on admission, left ventricular volume indices were higher in the high VEGF group than in the low VEGF group at the subacute phase of AMI (14 days). These differences were no longer present in the chronic phase of AMI. ConclusionPlasma VEGF levels were increased in patients with AMI, and peak levels were associated with left ventricular volume indices in the subacute phase, suggesting an important role of endogenous VEGF in the left ventricular dimension in patients with AMI.

Vascular endothelial growth factor A gene expression level is higher in patients with major depressive disorder and not affected by cigarette smoking, hyperlipidemia or treatment with statins.

Elevated levels of vascular endothelial growth factor (VEGF) are observed in conditions with vessel and neuron damage or pathological arborization and can therefore be detected in chronic inflammatory process, cardiovascular disease and depression. Hyperlipidemia and cigarette smoking are two factors that have been implicated in endothelial damage. The high comorbidity between cardiovascular disease and major depression disorder (MDD) prompted us to study the effect of cigarette smoking, hyperlipidemia and statin treatment on the VEGFA mRNA and protein expression levels measured in MDD patients. We analyzed 38 MDD patients and 38 healthy control individuals and observed that the MDD group had a significantly higher VEGFA mRNA level and protein serum concentration (P=0.001; P<0.001, respectively). We found no significant association between VEGFA expression at the mRNA or protein level and cigarette smoking, hyperlipidemia or treatment with statins (P>0.05). Interestingly, patients who had attempted suicide had a lower VEGF serum level compared with patients who had not attempted suicide. The translational value of this finding remains unknown. A higher VEGF concentration may play a potentially significant role in the pathogenesis of depression, and the expression level appears to be unaffected by additional factors.

Methodological differences account for inconsistencies in reported free VEGF concentrations in pregnant rats

Free vascular endothelial growth factor (VEGF) is undetectable in plasma during human pregnancy. However, studies examining pregnant rats have reported both low (8-29 pg/ml) and high (527-1,030 pg/ml) free VEGF. These discrepancies cast uncertainty over the use of rat models to study angiogenic factors in pregnancy and preeclampsia. This study investigates methodological factors that may explain these discrepancies. Plasma VEGF in nonpregnant, day 7 pregnant, and day 19 pregnant rats was measured using rat and mouse ELISAs (R&D Systems). The rat ELISA detected VEGF in plasma from nonpregnant rats but not in plasma from day 19 pregnant rats. The mouse ELISA detected higher VEGF concentrations than the rat ELISA in every sample tested. This discrepancy was greater in day 19 pregnant rats (median: 2,273 vs. 0 pg/ml) than in nonpregnant (97 vs. 20 pg/ml) and day 7 pregnant (66 vs. 2 pg/ml) rats. Recovery of recombinant rat VEGF (rrVEGF) spiked into plasma from nonpregnant and day 7 pregnant rats was high for the rat ELISA (82-105%) but low for the mouse ELISA (17-22%). The rat ELISA did not recover rrVEGF in plasma from day 19 pregnant rats, suggesting that this ELISA measures free VEGF. The use of the rat versus mouse ELISA likely explains the differences in reported VEGF concentrations in pregnant rats. While the rat ELISA appears to measure free VEGF, plasma concentrations in nonpregnant and pregnant rats are below the assay sensitivity limit. As most previous studies of pregnant rats used the mouse VEGF ELISA, these data should be interpreted cautiously.

Role of vascular endothelial growth factor in clinically localized prostate cancer treated with radiation therapy.

Anti-vascular endothelial growth factor (Anti-VEGF) agents are a promising approach to increase the efficacy of treatment for treatment-resistant prostate cancer. To correlate vascular endothelial growth factor (VEGF) expression and outcome following radiation therapy in the treatment of clinically localized prostate cancer. Retrospective observational study. Forty-one patients and clinically localized disease that were treated with radiation therapy were analyzed. For VEGF expression, immunoreactivity scores (IRS) were calculated using percent scores and intensity scores. Twenty-four patients were classified as having low (0 to 4 IRS) and 17 patients were classified as having high (5 to 8 IRS) VEGF expression. The median age was 71 years, median follow-up was 5.4 years and median radiation therapy dose was 70 Gy. VEGF expression was calculated as low in 24 patients and high in 17 patients. Higher VEGF expression was observed in 6/26 patients with a low Gleason score versus 11/15 patients with a high Gleason score (p=0.02). Biochemical failure (BF) was observed in 2/24 patients with low VEGF expression versus 7/17 patients with high VEGF expression (p=0.01). In univariate analysis, having a higher Gleason score (p<0.01), being in the high risk group (p=0.03) and having higher VEGF expression (p=0.01) predicted BF after definitive radiation therapy. The biochemical failure-free survival rate at 5 years tended to be different (91% vs. 53%) when patients were grouped according to VEGF expression (p=0.06). In attempt to define patients with clinically localized disease that are not sensitive to standard treatment modalities, cellular and/or molecular biological markers may be required.

Amyotrophic lateral sclerosis after embolization of cerebral arterioveneous malformations

Cerebral arterioveneous malformations (AVM) can cause neurological symptoms and carry a risk of hemorrhage. Therapeutic options to cure or reduce AVM include surgery, embolization, irradiation, and combinations thereof. Prompted by three index cases treated in our center, we studied whether AVM embolization is associated with an increased risk of subsequent amyotrophic lateral sclerosis (ALS). In a monocenter series, we retrospectively analyzed the new development of ALS in patients who had been treated with embolization of cerebral AVM from 1986 to 2010 (n = 1,114). After a median follow-up of 11 years (range, 0-25 years) after first embolization, seven patients developed ALS with a median latency of 14 years (range, 12-17 years) and a median age of ALS onset of 38 years (range, 28-52 years). In all cases, the initial limb of ALS symptom onset was ipsilateral to the AVM. Five patients died within the follow-up period, with a range of 1-4 years after the onset of ALS symptoms. The seven patients belonged to a subgroup of 34 patients who had in common a rare AVM architecture characterized by significant perinidal angiogenesis. All cases were partially treated by at least three embolization sessions. As there is no known association between AVM and ALS, AVM embolization must be taken into account to have contributed to the development of ALS in the seven patients with this rare AVM architecture. Searching for underlying mechanisms, we compared frozen serum samples that were available from four of the patients who developed ALS, from eight patients with AVM of other architecture, and less than three embolizations who did not develop ALS, and of 20 controls. The concentration of vascular endothelial growth factor (VEGF) in the serum was lowest in AVM patients who developed ALS (245 ± 154 pmol/l) and highest in controls (409 ± 178 pmol/l). Although this difference was not statistically significant in the small sample, it suggests that low VEGF production by AVM with significant angiogenesis, possibly due to multiple embolization procedures, might have contributed to ALS development. ALS should be considered as a late complication of multiple embolizations of cerebral AVM characterized by significant perinidal angiogenesis.

Clinical significance of serum vascular endothelial growth factor in patients with multiple myeloma

This study was purposed to investigate the relation of serum vascular endothelial growth factor (VEGF) levels with clinical types and therapeutic efficacy of multiple myeloma (MM), and to analyze the significance of VEGF in MM. The levels of serum VEGF were detected by enzyme-linked immunosorbent assay (ELISA) technique in 76 patients with MM. The relationship between the serum VEGF levels with MM patients' age, stages, types, and efficacy were analyzed. The results showed that the patients who were less than 65 years old had higher serum VEGF levels than elder patients, however, the difference between them had no statistical significance (P > 0.05). The VEGF level was the highest in IgG type patients, and then in light chain type, lowest in IgA type, however there were no statistical differences between them (P > 0.05). Patients of DS stage III had higher VEGF level than that of stage II, and there was also no statistical difference (P > 0.25). Patients of ISS stage I had lower VEGF level than that of stage II and III, and it also showed no statistical difference (P > 0.05). After treatment, patients obtained complete remission (CR) or very good partial remission (VGPR) had decrease of serum VEGF level, however, patients obtained less than partial remission (PR) had increase of serum VEGF level. Patients were divided into two groups according serum VEGF level ( ≤ 150 ng/L), patients with high VEGF levels had short overall survival time, there was statistical difference (P = 0.03). It is concluded that the serum VEGF level of MM patients dose not relate with age, clinical stages and M protein types; however, there was a certain association between overall survival and serum VEGF level, and the later may be one of poor prognostic factors.