Plasma Vascular Endothelial Growth Factor Levels Research Articles

A Compartment Model of VEGF Distribution in Humans in the Presence of Soluble VEGF Receptor-1 Acting as a Ligand Trap

Vascular endothelial growth factor (VEGF), through its activation of cell surface receptor tyrosine kinases including VEGFR1 and VEGFR2, is a vital regulator of stimulatory and inhibitory processes that keep angiogenesis – new capillary growth from existing microvasculature – at a dynamic balance in normal physiology. Soluble VEGF receptor-1 (sVEGFR1) – a naturally-occurring truncated version of VEGFR1 lacking the transmembrane and intracellular signaling domains – has been postulated to exert inhibitory effects on angiogenic signaling via two mechanisms: direct sequestration of angiogenic ligands such as VEGF; or dominant-negative heterodimerization with surface VEGFRs. In pre-clinical studies, sVEGFR1 gene and protein therapy have demonstrated efficacy in inhibiting tumor angiogenesis; while in clinical studies, sVEGFR1 has shown utility as a diagnostic or prognostic marker in a widening array of angiogenesis–dependent diseases. Here we developed a novel computational multi-tissue model for recapitulating the dynamic systemic distributions of VEGF and sVEGFR1. Model features included: physiologically-based multi-scale compartmentalization of the human body; inter-compartmental macromolecular biotransport processes (vascular permeability, lymphatic drainage); and molecularly-detailed binding interactions between the ligand isoforms VEGF121 and VEGF165, signaling receptors VEGFR1 and VEGFR2, non-signaling co-receptor neuropilin-1 (NRP1), as well as sVEGFR1. The model was parameterized to represent a healthy human subject, whereupon we investigated the effects of sVEGFR1 on the distribution and activation of VEGF ligands and receptors. We assessed the healthy baseline stability of circulating VEGF and sVEGFR1 levels in plasma, as well as their reliability in indicating tissue-level angiogenic signaling potential. Unexpectedly, simulated results showed that sVEGFR1 – acting as a diffusible VEGF sink alone, i.e., without sVEGFR1-VEGFR heterodimerization – did not significantly lower interstitial VEGF, nor inhibit signaling potential in tissues. Additionally, the sensitivity of plasma VEGF and sVEGFR1 to physiological fluctuations in transport rates may partially account for the heterogeneity in clinical measurements of these circulating angiogenic markers, potentially hindering their diagnostic reliability for diseases.

Effects of an anti‐VEGF administration on whole‐body VEGF distribution assessed by a molecularly‐detailed pharmacokinetic model: a cancer study

Vascular endothelial growth factor (VEGF), a potent cytokine stimulating angiogenesis, has been reported to be overexpressed in cancer making it a good target for anti‐angiogenic treatment. We constructed a molecularly‐detailed in silico model composed of three compartments (blood plus healthy and diseased tissues). Our model provides insights on the VEGF distribution in each compartment and serves to investigate the possible origins of the plasma VEGF increase observed in cancer patients. We also use this model to predict the effects of anti‐VEGF treatment through different modes of injection (slow infusion, metronomic therapy) on the VEGF profile in each compartment. We find that: 1) an increase of VEGF secretion by the tumor and/or an increase in vascular permeability of VEGF in tumor cannot solely explain the several‐fold plasma VEGF increase observed in cancer patients; 2) the introduction of an anti‐VEGF agent leads to a new pseudo‐steady‐state plasma VEGF level when administered in a metronomic fashion. These findings provide new insights and can be applied to optimizing anti‐angiogenic therapies targeting VEGF.

Increased circulating placental growth factor during percutaneous coronary intervention is associated with applied radiocontrast agent

Recent studies have suggested placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) as promising new biomarkers for risk stratification in acute coronary syndromes (ACS). However, little is known about the influence of percutaneous coronary intervention (PCI) on circulating PlGF and VEGF levels. Thirty-five patients with ACS, 27 patients with stable coronary artery disease (sCAD), and nine healthy controls were enrolled in the study. Although all patients with ACS and 14 patients with stable angina pectoris underwent PCI, 13 patients with coronary artery disease required no revascularization (sCAD). PlGF and VEGF plasma concentrations were measured by immunoassay during and at the end of PCI and coronary angiography. Plasma PlGF levels were comparable in patients with ACS and sCAD on admission. Although coronary angiography or heparin alone did not alter PlGF and VEGF levels, immediately after PCI a dramatic increase was seen in circulating PlGF and a decrease in VEGF, which was independent of the clinical presentation of the patients, heparin administration, or the angiographic procedure itself, but was associated with the extent of coronary artery disease and the amount of the injected contrast media. In-vitro experiments revealed that radiocontrast agents induced the release of PlGF from endothelial cells without altering PlGF mRNA expression. Patients undergoing PCI exhibit an increase in circulating PlGF, probably caused by posttranslational modifications of radiocontrast agents in endothelial cells. Therefore, analysis of plasma PlGF and VEGF levels may consider the timing of blood sampling with respect to PCI and contrast media exposure.

Correlation of electroretinography b-wave absolute latency, plasma levels of human basic fibroblast growth factor, vascular endothelial growth factor, soluble fatty acid synthase, and adrenomedullin in diabetic retinopathy

Background We investigated the b-wave latency of electroretinogram (ERG), human basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), soluble fatty acid synthase (s-Fas), and adrenomedullin (ADM) in diabetic retinopathy. Patients and Methods Thirty control and 60 type II diabetic women (mean age 45±3.9 years, duration of diabetes 10.1±2.1 years) were investigated. Diabetics without complications (Group II) and with retinopathy (Group III) were diagnosed depending on clinical findings, abnormal fundus examination, and ERG. Plasma levels of b-FGF, VEGF, s-Fas, and ADM were measured. Results ERG showed a significant increase of b-wave absolute latency, plasma b-FGF, VEGF, s-Fas, and ADM in diabetic retinopathy ( P<.05). A positive correlation was found between b-wave latency and VEGF and s-Fas, and a negative correlation with b-FGF and ADM. Conclusion This study elucidates the causative role of VEGF and s-Fas in diabetic retinopathy. VEGF may potently promote growth of endothelial cells and formation of new vessels implicated in proliferative retinopathy. s-Fas could be involved in advancement of apoptotic changes in retinopathy and high levels of b-FGF, and ADM may be compensatorily neuroprotective and vasculoprotective. The results showed that diabetic retinopathy is the result of multiple factors, so it is optimistic to believe that reversing VEGF or s-Fas will halt retinopathy, targeting multiple mechanisms simultaneously by administering combination treatments of VEGF antagonists; antiapoptotic drugs together with b-FGF and/or ADM may be prospective.

Plasma indices of angiogenesis in rheumatoid disease: Relationship to cardiovascular risk factors and cardiac function

Rheumatoid Disease (RD) is associated with increased rates of cardiovascular disease (CVD). Angiogenesis is central to RD, and well-recognized in CVD. We hypothesised that plasma levels of two indices associated with angiogenesis, vascular endothelial growth factor (VEGF) and angiogenin, would be higher among RD patients compared to healthy controls (HC), would relate to CVD risk factors, calculated 10-year coronary heart disease (CHD) and stroke risk scores. 144 clinic patients with established RD and 63 HC were recruited in a cross-sectional study. RD patients were grouped according to the presence (RD-CVD, n=73 or absence (non-CVD RD; n=71) of CVD risk factors. Angiogenin and VEGF levels were quantified by ELISA. There were no significant differences for VEGF or angiogenin, between RD-CVD, non-CVD RD and HC groups (p=NS). Calculated risks for both CHD (p=0.017) and stroke (p=0.016) were higher when RD-CVD was compared to non-CVD RD and HC. Upon multivariate analysis, methotrexate use (p=0.006) and prior mycocardial infarction (MI) (p=0.034) were associated with higher angiogenin levels; body mass index (BMI) (p=0.034) and presence of RD (p=0.029) itself predicted lower levels. For RD patients, serum creatinine (p<0.001) and CRP levels, VEGF levels, and NSAID/COX2 inhibitor use (all p<0.05) were independently associated with CHD risk; plasma VEGF and serum creatinine levels were independently associated with stroke risk (p<0.05). Although levels of angiogenin were not significantly different between HC and RD patients, RD may have some influence on their variation. Methotrexate use and prior MI predicted higher angiogenin levels, whilst levels of VEGF were negatively associated with 10-year CHD and stroke risk.

Vascular endothelial growth factor and acute mountain sickness

Study Objective:Despite causing significant morbidity throughout the mountainous regions of the world, the pathophysiology of acute mountain sickness (AMS) remains poorly understood. This study aims to improve the understanding of altitude illness by determining if vascular endothelial growth factor (VEGF) plays a role in the development of AMS. The purpose of this study was to determine if elevated plasma VEGF correlates with increased symptoms of AMS at high altitude.Patients and Methods:This is a prospective study of a cohort of healthy climbers on Denali (Mount McKinley) in Alaska at 14, 200 feet. Baseline demographics, medications, rates of ascent, and AMS scores were recorded. Pulse oximetry measurements and venous blood samples were obtained. Comparisons were made between mountaineers with and without AMS.Results:Seventy-two climbers were approached for participation in the study; 21 (29%) refused. Of the 51 climbers participating in the study, 14 subjects (27.5%) had symptoms of AMS and 37 subjects (72.5%) were free of symptoms of AMS. Plasma VEGF levels were 79.14 pg/dl (SD: 121.44) and 57.57pg/dl (SD: 102.71) in the AMS and non-AMS groups, respectively. These results were nonsignificant. Similarly, comparison of sex, age, rate of ascent, pulse oximetry values, or history of altitude illness did not reveal significant differences between the AMS and non-AMS groups.Conclusion:This study does not provide evidence in support of the theory that plasma VEGF correlates with symptoms of AMS.

VEGF 936C &gt; T Polymorphism and Association of BI-RADS Score in Women with Suspected Breast Cancer

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumors. A 936C > T polymorphism in the VEGF gene has been associated with reduced VEGF plasma levels. Purpose of the present study was to analyze the potential association between VEGF genotype and radiological appearance of breast lesions by mammography. Fifty two women with 54 suspected breast lesions were analyzed by the use of mammography with the standard breast imaging reporting and data systems (BI-RADS). Germline VEGF genotype was determined in all subjects by allele-specific digestion of amplification products. An open biopsy was performed on all lesions. VEGF CC, CT and TT genotypes were found in 41 (79%), 9 (17%) and 2 (4%) patients. By mammography 26, 16 and 12 suspected breast lesions were classified as BI-RADS scores 3, 4 and 5, respectively. Both carriers of the TT genotype were classified as BI-RADS 5, whereas among CT or CC carriers, BI-RADS scores 3, 4 and 5 were found in 26, 16 and 10 subjects (P < 0.026). The VEGF 936C > T polymorphism seems to be associated with a high BI-RADS score in women with suspicious breast lesions.

Vitreous Levels of Interleukin-6 and Vascular Endothelial Growth Factor in Macular Edema with Central Retinal Vein Occlusion

To investigate whether interleukin (IL)-6 or vascular endothelial growth factor (VEGF) influences macular edema in patients with central retinal vein occlusion (CRVO). Retrospective case-control study. Twenty-seven patients who had macular edema with CRVO and 16 patients with nonischemic ocular diseases (control group). Retinal ischemia was evaluated by measuring the area of capillary nonperfusion using fluorescein angiography and the public domain Scion Image program, and macular edema was examined by optical coherence tomography. Vitreous fluid samples were obtained at pars plana vitrectomy. VEGF and IL-6 levels in vitreous fluid and plasma were determined with enzyme-linked immunosorbent assay kits. Vitreous fluid levels of IL-6 and VEGF. The vitreous fluid levels of VEGF (median: 435 pg/ml) and IL-6 (median: 51.2 pg/ml) were significantly higher in the patients with CRVO than in the control group (median: 62.4 pg/ml and 1.07 pg/ml, respectively; P = 0.0046 and P<0.0001, respectively). The vitreous fluid level of VEGF was significantly correlated with that of IL-6 (P = 0.0029). Vitreous fluid levels of both VEGF and IL-6 were significantly higher in patients with CRVO who had retinal ischemia than in those without ischemia (P<0.0001 and P = 0.0003, respectively). Vitreous fluid levels of VEGF and IL-6 were also significantly correlated with the severity of macular edema (P = 0.0014 and P = 0.0047, respectively). Both IL-6 and VEGF were elevated in the vitreous fluid of patients with ischemic CRVO and macular edema. VEGF may increase vascular permeability in patients with macular edema and CRVO, whereas IL-6 may also contribute by acting together with or via VEGF. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Changes of aqueous vascular endothelial growth factor and interleukin‐6 after intravitreal triamcinolone for branch retinal vein occlusion

To investigate sequential changes of aqueous vascular endothelial growth factor (VEGF) and interleukin (IL)-6 in macular oedema secondary to branch retinal vein occlusion after single intravitreal injection of triamcinolone acetonide (IVTA). We recruited 10 healthy controls and 30 patients at Chonnam National University Hospital, Gwangju, Korea. Aqueous and plasma levels of VEGF and IL-6 were measured by enzyme-linked immunosorbent assay at the time of IVTA and 3 months later. Non-response to IVTA was defined as showing persistent macular oedema based on a reduction of central macular thickness by less than 20% from baseline measurements by optical coherence tomography and vision improvement by less than 0.3 logMAR. Fluorescein angiography was performed 6 months after IVTA. We compared aqueous levels of VEGF and IL-6 between responders and non-responders. The aqueous levels of VEGF and IL-6 were significantly higher in 12 non-responders than in 18 responders at baseline measurements (511 +/- 245 pg/mL vs. 230 +/- 108 pg/mL, P < 0.001; 38 +/- 31 pg/mL vs. 16 +/- 13 pg/mL, P < 0.001, respectively). Aqueous levels of VEGF were still higher in non-responders (312 +/- 64 pg/mL) 3 months after IVTA, and aqueous levels of VEGF in responders returned to normal (86 +/- 21 pg/mL, P < 0.001). Aqueous levels of IL-6 normalized in all patients 3 months after IVTA. Fluorescein angiography revealed that non-responders showed higher frequencies of macular ischaemia and ischaemic branch retinal vein occlusion. IL-6-independent VEGF secretion may contribute to persistent macular oedema associated with ischaemic BRVO after IVTA.

Quantitative Analysis of Vascular Endothelial Growth Factor in Liver Metastases from Pancreatic Carcinoma as a Predictor of Chemotherapeutic Effect and Prognosis

In pancreatic carcinoma, vascular endothelial growth factor (VEGF) expression at the primary site has been suggested to be a prognostic parameter. We quantitatively analyzed VEGF expression in liver metastases from pancreatic carcinoma and examined the correlation among VEGF expression in liver metastases, clinicopathologic factors, and clinical outcome. The subjects consisted of 23 patients with pancreatic adenocarcinoma who had liver metastases and were treated with S-1 and gemcitabine as the first-line treatment. VEGF expression was quantitated by enzyme immunoassay in biopsy specimens of liver metastases and nontumorous liver tissue, and in plasma. In 10 of the 23 patients, VEGF expression was also quantitated in biopsy specimens of the primary pancreatic tumor. All samples were collected before treatment. The VEGF level in nontumorous liver tissue was 36.6 +/- 10.0 pg/mg protein versus 376.8 +/- 106.1 pg/mg protein in liver metastases (P = 0.0016). Pretreatment VEGF levels in plasma and in primary pancreatic carcinoma did not correlate with VEGF levels in the corresponding liver metastases. The median VEGF level in liver metastases (138.9 pg/mg protein) was used as the cutoff value between high and low VEGF expression in liver metastases. Patients showing high VEGF expression had a significantly longer progression-free survival and overall survival than patients showing low VEGF expression in liver metastases (P = 0.0219 and P = 0.0074, respectively). Evaluation of VEGF levels in liver metastases might be useful in assessing the prognosis of patients with metastatic pancreatic carcinoma who are under systemic chemotherapy.

Kidney-derived mesenchymal stem cells contribute to vasculogenesis, angiogenesis and endothelial repair

We isolated a clonal cell line (4E) from kidneys of mice expressing green fluorescent protein controlled by the endothelial-specific Tie2 promoter. When grown in a three-dimensional matrigel matrix they formed a fluorescent capillary network. In vivo angiogenesis assays using growth factor-depleted matrigel implanted plugs promoted a moderate angiogenesis of host endothelial cells. Using vascular endothelial growth factor (VEGF)-A and fibroblast growth factor-2 in the plugs containing 4E-cells resulted in a robust vasculogenesis. Transplantation of 4E cells into mice with acute renal ischemia showed selective engraftment in the ischemic kidney which promoted tubular regeneration by increasing epithelial proliferation and inhibiting apoptosis. This resulted in an accelerated functional recovery 3 days after ischemia. These mice showed a 5-fold increase in tissue VEGF expression compared to controls, but no difference in plasma VEGF level corresponding with better preservation of peritubular capillaries, perhaps due to a local paracrine effect following systemic 4E infusion. One month after ischemia, 9% of engrafted 4E cells expressed green fluorescent protein in the peritubular region while half of them expressed alpha-smooth muscle actin. Our study shows that kidney mesenchymal stem cells are capable of differentiation toward endothelial and smooth muscle cell lineages in vitro and in vivo, support new blood vessel formation in favorable conditions and promote functional recovery of an ischemic kidney.

Vascular endothelial growth factor levels in newborns with meconium stained amniotic fluid

The effects of meconium-stained amniotic fluid (MSAF) on cord blood vascular endothelial growth factor (VEGF) levels have not been explored. The aim of this study was to verify whether MSAF influences cord blood VEGF levels in healthy term neonates and we can use cord blood VEGF levels in infants with MSAF as an indicator of fetal distress. Using an enzyme-linked immunosorbent assay double sandwich method, plasma VEGF levels were determined in 18 healthy term neonates with MSAF and in 16 healthy term neonates without MSAF. VEGF plasma levels were not significantly different between healthy term neonates with or without MSAF. Intrauterine meconium passage could not affect VEGF levels on cord blood in term newborn infants and VEGF level may not be used as an indicator of fetal distress in infants with MSAF.

Use of meloxicam for OHSS prevention

OBJECTIVE: Vascular endothelial growth factor (VEGF) plays a central role in Ovarian hyperstimulation syndrome (OHSS) by increasing vascular permeability. Recently, we have demonstrated a beneficial effect of meloxicam by reducing ovarian weight and VEGF expression associated with OHSS in a rat model. This effect may be mediated by the Ciclooxigenase-2 (COX-2), which is inhibited by meloxicam. The objective is to assess the role of Meloxican in OHSS prevention in oocyte donors. DESIGN: Prospective randomized study. MATERIALS AND METHODS: 36 oocyte donors with OHSS risk after COH were randomized to either receive expectant clinical management and support (group 1, n=18), or Meloxicam treatment (15 mg/daily orally for 8 days starting on the day of oocyte retrieval) (Group 2, n=18). All donors met standard ASRM screening criteria (with written informed consent signed, age between 21 and 30 years, and basal FSH levels ≤ 12 IU/l). OHSS risk parameters as inclusion criteria were: ≥ 10 follicles at least 14 mm per ovary and E2 levels ≥ 2500 pg/ml on hCG day. All patients used agonist GnRh luteal phase protocol, with rFSH 250 IU/daily for 4 days followed by equal dose of hMG for ovarian stimulation. Both groups were clinically, hematologically and biochemically followed for signs and symptoms of OHSS and received supportive measures as required. Blood samples for VEGF measurement were obtained on the day of hCG and 7 days later. RESULTS: Mean age, BMI, oocytes retrieved and estradiol levels were comparable between both groups as well as plasma VEGF concentrations on hCG day (19.1 ± 8.9 pg/ml and 24.6 ± 12.1 pg/ml for Groups 1 and 2 respectively, NS); although seven days after hCG, VEGF plasma levels were significantly lower in the treatment group (22.3 ± 10.9 pg/ml vs 13.7 ±6.3 pg/ml for Groups 1 and 2 respectively; p<0.05). Additionally, we found less OHSS symptoms in Group 2 patients (4/18 with slight abdominal distention; 2/18 with mild ascites), while in Group 1 their symptoms persisted unchanged or slightly worse on day 7 (14/18 with slightly abdominal distention; 12/18 presenting ascitis). CONCLUSIONS: Our results suggest a beneficial effect of meloxicam in the prevention and treatment of OHSS and its complications in ART cycles when no embryos are transferred. More studies are necessary in order to analyze the risk-benefit ratio of meloxicam administration in IVF embryo-tranfer cycles, since its use has been related to an antiimplantatory effect.

VEGF Secretion is Inhibited by Interferon-Alpha in Several Melanoma Cell Lines

Interferon-alpha (IFN-alpha) is employed in the treatment of malignant melanoma; however, it mediates regression of disease in only 10-15% of patients. Currently, its mechanism of action is uncharacterized. Low-dose IFN-alpha exerts anti-angiogenic effects when used in the treatment of life-threatening hemangiomas of infancy, suggesting anti-angiogenesis as a mechanism of action. IFN-alpha may exert its anti-tumor effect in the setting of advanced malignancy by inhibiting the secretion of vascular endothelial growth factor (VEGF), a pro-angiogenic substance. We hypothesized that IFN-alpha would decrease the release of VEGF by melanoma tumors. We studied the effect of IFN-alpha on VEGF production in nine human melanoma cell lines. We also examined VEGF levels in 49 patients with advanced malignancies who received low-dose IFN-alpha and interleukin-12 (IL-12) on an NCI-sponsored phase I trial. Human melanoma cell lines produced varying amounts of VEGF in vitro (60-1500 pg/mL at 48 h). Certain melanoma cell lines such as 18105 MEL secreted low levels of VEGF (152 pg/mL) after 48 h of culture, whereas other lines secreted very high levels (FO-1 3,802 pg/mL). Treatment of melanoma cells with IFN-alpha (2000 U/mL) decreased VEGF secretion by 40-60% in VEGF-high cell lines; however, this effect was not demonstrated in VEGF-low cell lines. In cancer patients, pretreatment VEGF plasma levels varied from 471 to 4200 pg/mL. A decrease in VEGF plasma levels after treatment directly correlated with the number of treatment cycles administered (Pearson correlation, p = 0.04). In summary, IFN-alpha inhibits VEGF secretion by melanoma cell lines in vitro and may have similar actions in malignancies that respond to IFN-alpha treatment.

Genetic polymorphisms of VEGF, interactions with cigarette smoking exposure and esophageal adenocarcinoma risk

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis in esophageal adenocarcinoma (EA). Polymorphisms in the VEGF gene have been associated with altered VEGF expression and plasma VEGF levels. We hypothesized that polymorphisms of VEGF may contribute to EA risk. Functional polymorphisms in the VEGF gene (-460C/T, +405C/G and +936C/T) were determined in 308 patients with EA and 546 healthy controls. Logistic regression analysis was employed to assess the associations between genotypes, haplotypes of VEGF and EA risk, adjusting for multiple confounding factors. Compared with the +936CC genotype, the combined +936CT+TT genotypes were significantly associated with increased risk of developing EA, with adjusted odds ratio (OR) = 1.49 [95% confidence interval (CI), 1.05-2.12; P = 0.027]. The -460CT+CC were associated with increased risk of EA in smokers (adjusted OR = 1.57; 95% CI, 1.07-2.30; P = 0.021), whereas the -460CT/CC were associated with decreased risk of EA (adjusted OR = 0.47; 95% CI, 0.25-0.91; P = 0.025) in non-smokers. Compared with non-smokers with the +460TT, smokers with the +460CT+CC had significantly higher risk of EA (adjusted OR = 3.32; 95% CI, 1.56-7.10; P = 0.002). No overall or interacting association with EA risk was found for the +405C/G polymorphism. Haplotype CGT (-460C/+405G/+936T) was significantly associated with higher risk of EA (adjusted OR = 1.70; 95% CI, 1.04-2.73; P = 0.034). These results suggested that cigarette smoking modifies the association between VEGF polymorphisms and EA risk among Caucasians.

Phase II Evaluation of Imatinib Mesylate in the Treatment of Recurrent or Persistent Epithelial Ovarian or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study

This phase II trial assessed the activity and tolerability of an oral dose of imatinib mesylate 400 mg twice daily in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma. The association between the expression of certain markers and clinical outcome was investigated. Primary measure of clinical efficacy was progression-free survival (PFS) at 6 months. Mutational analysis of KIT, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay for markers (KIT, platelet-derived growth factor [PDGF] receptor [-R], AKT2, phosphorylated AKT [p-AKT], stem cell factor [SCF], and PDGF) were performed. Fifty-six eligible patients were evaluated. Nine patients were progression free for at least 6 months including one complete responder. The median PFS and survival were 2 and 16 months, respectively. The most common grade 3 and 4 toxicities were neutropenia, GI, dermatologic effects, pain, and electrolyte disturbances. At least one target of imatinib (KIT, PDGFR-alpha, or PDGFR-beta) was expressed in all tumors, and most tumors expressed all three receptors. Higher expression of p-AKT and PDGFR-beta were associated with shorter PFS, and higher IHC scores (% immunopositive cells x staining intensity) of SCF and p-AKT were associated with decreased overall survival. No sequence mutations were detected in the KIT gene. Higher pretreatment plasma concentrations of PDGF-AB, PDGF-BB, and vascular endothelial growth factor (VEGF) were individually associated with shorter PFS and survival. Imatinib mesylate was well tolerated but had minimal single-agent activity in patients with recurrent ovarian or primary peritoneal carcinoma. No marker was identified that would predict activity of imatinib; however, tumor p-AKT and plasma VEGF levels were associated with poor outcome.

Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients

Background:Angiopoietin-2 and vascular endothelial growth factor (VEGF) may impair vascular barrier function while angiopoietin-1 may protect it. It was hypothesised that circulating angiopoietin-2 is associated with pulmonary permeability oedema and...

Plasma Levels of Vascular Endothelial Growth Factor After Treatment for Cerebral Arteriovenous Malformations

The role of abnormal angiogenesis in the formation and progression of cerebral arteriovenous malformations (AVMs) is unclear. Previous studies have demonstrated increased local expression of vascular endothelial growth factor (VEGF) in AVM tissue and increased circulating levels of VEGF in AVM patients. We sought to further investigate the role of VEGF in AVM pathophysiology by examining changes in plasma VEGF levels in patients undergoing treatment for AVMs. Three serial blood samples were obtained from 13 AVM patients undergoing treatment: (1) before any treatment, (2) 24 hours postresection, and (3) 30 days postresection. Plasma VEGF concentrations were measured via commercially available enzyme-linked immunosorbent assay (ELISA). For controls, blood samples were obtained from 29 lumbar laminectomy patients. The mean plasma VEGF level in AVM patients at baseline was 36.08+/-13.02 pg/mL, significantly lower than that of the control group (80.52+/-14.02 pg/mL, P=0.028). Twenty-four hours postresection, plasma VEGF levels dropped to 20.09+/-4.54 pg/mL, then increased to 66.81+/-26.45 pg/mL 30 days later (P=0.048). The mean plasma VEGF concentration 30 days after resection was no longer significantly different from the control group (P=0.33). Plasma VEGF levels in 13 AVM patients were unexpectedly lower than controls, dropped early after AVM resection, then significantly increased 30 days later. These results support the key role of abnormal angiogenesis in AVM pathophysiology and suggest that a disruption in systemic VEGF expression may contribute to the natural history of these lesions.

Single nucleotide polymorphisms and haplotypes in the gene for vascular endothelial growth factor and risk of prostate cancer

Vascular endothelial growth factor (VEGF) plays a key role in the regulation of angiogenesis and has been related to cancer development and progression. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in prostate cancer, we performed a case–control study including 702 prostate cancer patients and 702 male age-matched healthy control subjects. Seven VEGF candidate polymorphisms were determined by 5′-nuclease (TaqMan) assays. Furthermore, VEGF plasma levels and genotypes were analysed in a group of 64 healthy men. Haplotype analysis showed two separate blocks of high-linkage disequilibrium, formed by five polymorphisms upstream of the coding sequence (promoter and 5′-untranslated region) and two polymorphisms downstream of the coding sequence. None of the single polymorphisms or haplotypes was significantly associated with the presence of prostate cancer. In a multivariate regression analysis including age, VEGF genotypes and haplotypes as covariates and VEGF plasma level as dependent variable, none of the VEGF polymorphism or haplotypes was a significant predictor of VEGF plasma levels. The present data suggest that polymorphisms or haplotypes in the VEGF gene do not modify the risk of prostate cancer.

Discrepant levels of vascular endothelial growth factor in psoriasis patients treated with PUVA, Re‐PUVA and narrow‐band UVB

Previous reports showed that serum levels of vascular endothelial growth factor (VEGF) are increased in patients with psoriasis. However, to our knowledge, no studies have evaluated the effects of PUVA, Re-PUVA and narrow-band UVB (NB-UVB) treatments on serum levels of VEGF in patients with psoriasis. The aim of the study was to evaluate the influence of PUVA, Re-PUVA and NB-UVB treatments on angiogenic activities in patients with psoriasis by comparing serum levels of VEGF. Forty-six patients with psoriasis and 20 healthy subjects were included in the study. Peripheral blood samples were collected before, during and after the therapies. The efficacy of PUVA, Re-PUVA and NB-UVB was delineated by the psoriasis area and severity index. A repeated measure of ANOVA, Mann-Whitney U-test, chi(2) and Pearson's correlation coefficient were used for statistical analysis. The VEGF levels were significantly decreased in the PUVA group at the end of the follow-up period (P<0.001). However, the levels were significantly increased in the groups of NB-UVB and Re-PUVA (P<0.001). We found that there was a discrepancy during the PUVA, Re-PUVA and NB-UVB treatments. We believe that VEGF plasma levels could not be a useful monitor of psoriasis activity and/or treatment response.