Endothelial Growth Factor Plasma Research Articles

Serial Assessment of Growth Factors Associated with Liver Regeneration in Patients Operated with Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

Background: There is limited knowledge about the mechanisms behind the unparalleled growth of the future liver remnant (FLR) linked to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). In this study, liver regenerative markers were examined in patients subjected to ALPPS. Methods: Ten patients with colorectal liver metastases treated with neoadjuvant chemotherapy and ALPPS were included. Plasma was sampled at 6 time points and biopsies from both liver lobes were collected at both stages of ALPPS. The levels of interleukin (IL)-6, hepatocyte growth factor (HGF), tumor necrosis factor-α, epidermal growth factor, and vascular endothelial growth factor in plasma were measured at each time point. Expression of mRNA for markers of proliferation and apoptosis was studied in the biopsies from both liver lobes taken at both stages. Results: ALPPS resulted in a peak of IL-6 after stage 1 (p = 0.004), which decreased rapidly and did not increase again after stage 2. HGF also increased after stage 1 (p = 0.048), and the HGF levels correlated significantly with the degree of growth of the FLR before stage 2 (p = 0.02, r² = 0.47). There was a correlation between peak levels of IL-6 and HGF (p = 0.03, r² = 0.84). Conclusions: IL-6 and HGF seem to be early mediators of hypertrophy after stage 1 in the ALPPS procedure. The peak HGF plasma level correlates with the degree of FLR growth in patients subjected to ALPPS.

Arginine administration increases circulating endothelial progenitor cells and attenuates tissue injury in a mouse model of hind limb ischemia/reperfusion.

This study investigated whether the administration of L-Arginine, the precursor of nitric oxide, increases the percentages of blood endothelial progenitor cells and protects against ischemia/reperfusion induced inflammatory response in a mouse model of hind-limb IR injury. C57BL/6 mice were randomized to one normal-control and four ischemia/reperfusion groups. The normal-control group did not undergo an ischemia/reperfusion procedure but mice in the ischemia/reperfusion groups were subjected to 150 min of unilateral hind-limb ischemia. The ischemia/reperfusion groups were subjected to either intravenous saline or L-Arginine (300 mg/kg body weight) administration before reperfusion and then sacrificed at either 24 h or 48 h after reperfusion. Blood and muscle tissues were collected for analysis. Ischemia/reperfusion injury led to a significant decrease in the percentage of blood endothelial progenitor cells and plasma nitric oxide concentration but plasma interleukin-6 levels and gene expression of inflammatory cytokines in injured muscle tissue were elevated. In contrast to the saline groups, those with L-Arginine administration were able to maintain a normal level of blood endothelial progenitor cells. In addition, after reperfusion, concentrations of nitric oxide, matrix metallopeptidase-9, and vascular endothelial growth factor in plasma were upregulated but keratinocyte-derived chemokine and monocyte chemoattractant protein-1 messenger RNA expressions in muscle were attenuated 48 h after reperfusion. Histologic findings also demonstrated a significant reduction of ischemia/reperfusion-induced muscle injury when L-Arginine was administered. A single dose of L-Arginine administration before reperfusion increases the percentage of endothelial progenitor cells and reduces the inflammatory reaction locally and systemically after ischemia/reperfusion injury.

Vascular endothelial growth factor (VEGF-A) plasma levels in non-small cell lung cancer: relationship with coagulation and platelet activation markers.

Platelet activation, commonly found in lung cancer patients, may cause the release of angiogenic factors, such as vascular endothelial growth factor (VEGF-A). The present study was designed to investigate whether plasma VEGF-A levels were associated to different stages of non-small cell lung cancer (NSCLC). Moreover, sP-selectin, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complex (TATc) and D-dimer levels were measured to test the hypothesis of an involvement of platelet and coagulation activation in tumor angiogenesis. VEGF-A, sP-selectin, F1+2, TATc and D-dimer levels were elevated in 65 patients with NSCLC, particularly in metastatic patients. sP-selectin (p <0.003) and F1+2 (p <0.005) levels were independently associated to VEGF-A. In addition, patients with positive levels of both sP-selectin and F1+2 had the highest levels of VEGF-A. In conclusion, our findings support the hypothesis that thrombin generation might induce platelet activation and VEGF-A release in NSCLC.

Netrin-1 promotes mesenchymal stem cell revascularization of limb ischaemia.

This study examines the effect and mechanism of action of Netrin-1 on bone marrow mesenchymal stem cells in angiogenesis. Tube formation and migration of bone marrow mesenchymal stem cells were observed in cell culture. Bone marrow mesenchymal stem cells or Netrin-1-bone marrow mesenchymal stem cells were injected into the ischaemic area of the rat hind limb on the first day after surgery. Laser Doppler perfusion imaging was performed to analyse the levels of vascular endothelial growth factor in plasma and muscles, and immunohistochemistry and immunofluorescence were used to analyse angiogenesis. Bone marrow mesenchymal stem cells in medium containing Netrin-1 markedly increased the number of tubes formed and the migration of bone marrow mesenchymal stem cells compared with the untreated control group. The function of Netrin-1 in tube formation and migration is similar to vascular endothelial growth factor, and combined with vascular endothelial growth factor, Netrin-1 has more enhanced effect than in the other three groups. The Netrin-1-bone marrow mesenchymal stem cell group had better augmented blood-perfusion scores and vessel densities, as well as improved function of the ischaemic limb than that of the group injected with bone marrow mesenchymal stem cells (treated with bone marrow mesenchymal stem cells individually) or the control group (treated with medium). These results suggest that Netrin-1 has the ability to augment the angiogenesis of bone marrow mesenchymal stem cells and improve the function of the ischaemic hind limb by increasing the level of vascular endothelial growth factor.

Association of markers of bacterial translocation with immune activation in decompensated cirrhosis

Bacterial translocation (BT) may cause infections, in particular, spontaneous bacterial peritonitis (SBP). In the absence of overt infection, BT may further stimulate the immune system and contribute to haemodynamic alterations and complications. Bacterial DNA (bDNA) is claimed to be a promising surrogate marker for BT, although its clinical relevance has been questioned. In 38 cirrhotic patients with and without SBP, bDNA in blood and ascites were assessed by 16S rDNA quantitative PCR. Levels of lipopolysaccharide-binding protein in plasma and highly sensitive C-reactive protein, tumour necrosis factor-α, soluble urokinase plasminogen activating receptor, interleukin-6, interleukin 8, interferon-γ inducible protein-10 and vascular endothelial growth factor in plasma and ascites were measured by multiplex cytokine and ELISA assays. In patients without signs of SBP or positive cultures, we found a high frequency of bDNA but low concordance of bDNA between blood and ascites. Markers of inflammation were not significantly different between blood bDNA-positive (22%), ascites bDNA-positive (52%), and bDNA-negative patients. The 16S rDNA PCR failed to show bDNA in two out of six samples with SBP. Sequencing of positive samples did not determine the source of bDNA. bDNA as assessed by this PCR method was largely unrelated to markers of inflammation and does not seem to be of clinical value in the diagnosis of SBP. According to our results, bDNA is not a reliable marker of BT.

Elevated hydrogen sulfide levels in vitreous body and plasma in patients with proliferative diabetic retinopathy.

Hydrogen sulfide (H2S), a colorless gas, has been confirmed to be a gaseous messenger molecule and an endogenous stimulus for angiogenesis recently. This study was performed to investigate the role of H2S in diabetic retinopathy. Blood samples were collected from normal controls and patients with diabetes. Vitreous samples were collected from patients with proliferative diabetic retinopathy (PDR) and patients with rhegmatogenous retinal detachment. Patients were grouped into diabetic patients without diabetic retinopathy (non-DR), with nonproliferative DR, and with PDR. Concentrations of H2S and vascular endothelial growth factor in the plasma and vitreous body were detected using a spectrophotometer. A decreased H2S level in the plasma was observed in non-DR group (41.89 ± 8.52 μM, P < 0.05), and an increased H2S level in the plasma was observed in PDR group (60.49 ± 11.14 μM, P < 0.001), when compared with that in normal controls (49.67 ± 9.72 μM). There was no difference in plasma H2S level between patients with nonproliferative DR (54.13 ± 8.61 μM) and normal controls. In the vitreous body, H2S levels in PDR group were significantly higher (76.80 ± 24.08 μM, P < 0.001) than that in rhegmatogenous retinal detachment group (24.37 ± 11.25 μM). Levels of vascular endothelial growth factor in plasma from patients with diabetes were significantly lower (P < 0.001) than that in normal controls. Vascular endothelial growth factor levels in the vitreous body from diabetic patients with PDR were significantly higher (885.61 ± 190.41 pg/mL, P < 0.001) than that from patients with rhegmatogenous retinal detachment (89.98 ± 19.56 pg/mL). Seven days after an intravitreal injection of ranibizumab, a significantly decreased H2S level (55.58 ± 7.20 μM, P < 0.05) was observed in the vitreous body in patients with PDR when compared with that (75.07 ± 12.95 μM) in the vitreous body collected just before intravitreal injection. These results indicated that anti-vascular endothelial growth factor may downregulate the H2S level in the vitreous body, and H2S may play a role in the development of DR. Hydrogen sulfide may be a novel target for the therapy of DR.

Withdrawal of GnRH agonist decreases oestradiol and VEGF concentrations in high responders

This study evaluated whether the withdrawal of a gonadotrophin-releasing hormone (GnRH) agonist before triggering ovulation reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in high-risk infertility patients who were treated with gonadotrophins. GnRH agonist was withdrawn for 2 or 3 days when dominant follicles were ⩾14mm in diameter, according to the GnRH agonist long protocol. Non-withdrawal of GnRH agonist was used as control. The serum concentration of oestradiol on the ovulation trigger day was significantly decreased in the GnRH agonist withdrawal group compared with the control group (5750.78±2344.77pg/ml versus 8076.43±1981.67pg/ml); however, the number of retrieved oocytes and the fertilization rate were similar between the groups. In addition, the concentrations of vascular endothelial growth factor in plasma on day of human chorionic gonadotrophin administration and follicular fluid on the oocyte retrieval day were decreased following GnRH agonist withdrawal. In fresh embryo transfer cycles, rates of clinical pregnancy, implantation and OHSS were not different between the groups. When GnRH agonist withdrawal was followed by total embryos cryopreserved, the rate of OHSS was decreased compared with the control group (0% versus 8.70%). Clinical pregnancy rates in cryopreserved embryo transfer cycles were comparable between the two groups.This study was a prospective, clinical and laboratory study of 96 patients (corresponding to 96 cycles) with high antral follicle counts, who were at high risk for ovarian hyperstimulation. The study was carried out between May and September 2012. Gonadotrophin-releasing hormone (GnRH) agonist was withdrawn in 47 cycles for 2 or 3 days when the dominant follicles were ⩾14mm in diameter, according to the GnRH agonist long protocol. The non-withdrawal of GnRH agonist in 49 cycles was used as the control. The serum concentrations of oestradiol on the ovulation trigger day were significantly decreased in the GnRH agonist withdrawal group compared with the control group (5750.78±2344.77pg/ml versus 8076.43±1981.67pg/ml; P<0.001); however, the numbers of retrieved oocytes and fertilization rates were similar between the two groups. In addition, the concentrations of VEGF in plasma on the day of human chorionic gonadotrophin administration and follicular fluid on the oocyte retrieval day were decreased following GnRH agonist withdrawal. In fresh embryo transfer cycles, the rates of clinical pregnancy, implantation and ovarian hyperstimulation syndrome (OHSS) were not different between the two groups. When GnRH agonist withdrawal was followed by cryopreservation of all embryos, the rate of OHSS was decreased compared with the control group (0% versus 8.70%). Clinical pregnancy rates in vitrified–warmed embryo transfer cycles were comparable between the two groups. The appropriate withdrawal of GnRH agonist, before triggering ovulation, decreased the concentrations of oestradiol and VEGF in patients undergoing ovarian stimulation, which may reduce the incidence of ovarian hyperstimulation.

Pretreatment Levels of Vascular Endothelial Growth Factor in Plasma Predict a Complete Remission Rate and Time to Relapse or Progression in Patients with Diffuse Large B-Cell Lymphoma

The aim of this study was to verify whether pretreatment plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis and survival of patients with diffuse large B-cell lymphoma (DLBCL). Plasma VEGF levels were assessed at the time of diagnosis in 157 DLBCL patients treated with anthracycline-based chemotherapy. Plasma VEGF levels greater than or equal to the highest quartile (high VEGF levels) were associated with lower probability of a complete remission achievement (odds ratio 0.3; 95% confidence interval [CI]: 0.1-0.6; p = 0.002) in univariate as well as in multivariate analysis (p = 0.04). The estimated 3-year progression-free survival (PFS) rate of patients with high VEGF levels was 31.7% (95% CI 17-51) compared to the 62.5% 3-year PFS rate (95% CI 53-71; p = 0.0004) in the patients with lower values. The former group of patients demonstrated an estimated 3-year overall survival (OS) rate of 47.1% (95% CI 30-65) in contrast to the 3-year OS rate of 64.3% (95% CI 54-73; p = 0.02) in the latter. In multivariate analysis, the high VEGF level retained its independent impact on shorter PFS (p = 0.02). Our results suggest that VEGF plays an important role in the clinical course of DLBCL. VEGF may be a useful marker for selecting the patients for whom new treatment approaches, especially those based on VEGF inhibitors, could be recommended.

197P - Breast Cancer Patients Resistant to Endocrine Therapy are Immunodeficient and Show Enhanced Transforming Growth Factor - Beta and Vascular Endothelial Growth Factor in Plasma

197P - Breast Cancer Patients Resistant to Endocrine Therapy are Immunodeficient and Show Enhanced Transforming Growth Factor - Beta and Vascular Endothelial Growth Factor in Plasma

Mobilization of endothelial progenitor cells with exercise in healthy individuals: a systematic review.

Physical exercise mobilizes endothelial progenitor cells (EPCs) to peripheral blood. However, this effect seems to depend on exercise characteristics, such as duration and intensity. The aim of this systematic review was to verify the impact of a single bout of aerobic exercise on the mobilization of EPCs in healthy individuals, and the potential mechanisms involved. The bibliographic search was conducted on the following electronic databases in May 2011: SciELO, LILACS, Cochrane, ClinicalTrials.gov, SPORTDiscus and Medline. Of the 178 articles initially identified, 12 met the inclusion criteria and were classified regarding quality according to the PEDro scale. The magnitude and duration of the EPC mobilization response were higher after long/ultralong duration exercises, and they are correlated with vascular endothelial growth factor (VEGF) plasma levels. The EPC mobilization peak in response to a maximal or submaximal single bout of exercise lasting up to one hour occurs immediately after the exercise or within the first hour after it. One possible mechanism is nitric oxide (NO) bioavailability. The individuals' age and exercise intensity seem to interfere with the EPC mobilization response. Long/ultralong duration exercises promote more pronounced EPC mobilization as compared with maximal or submaximal exercises. The mechanisms involve VEGF release in long/ultralong duration exercises and NO bioavailability in maximal or submaximal exercises lasting less than one hour.

Vascular Endothelial Growth Factor in Plasma and Vitreous Fluid of Patients with Proliferative Diabetic Retinopathy Patients after Intravitreal Injection of Bevacizumab

To investigate plasma and vitreous vascular endothelial growth factor (VEGF) levels after intravitreal bevacizumab (IVB) injection into eyes with proliferative diabetic retinopathy (PDR). Retrospective, interventional, nonrandomized, comparative study. Fifty-six eyes of 56 patients with PDR and 13 eyes of 13 patients with nondiabetic ocular diseases were enrolled. Analysis included evaluation of basic clinical conditions and measurement of vitreous and plasma VEGF concentrations using enzyme-linked immunosorbent assays. PDR eyes without IVB had the highest vitreous VEGF levels; the levels were significant compared with those in the recent IVB group (previous injection within 1 week), the prolonged IVB group (injection more than 1 week previously), and the nondiabetic control group (P = .001, P = .035, P < .001, respectively). The vitreous VEGF level in the recent IVB group was higher than that in prolonged IVB group (P = .035). PDR eyes without IVB had the highest plasma VEGF level, and the level was significant compared with those in the recent IVB group, the prolonged IVB group, and the nondiabetic control group (P < .001, P = .003, P < .001, respectively). The plasma VEGF level in the recent IVB group was lower than that in the prolonged IVB group (P = .003). The vitreous VEGF level was associated significantly with the plasma VEGF level (P = .002). Vitreous and plasma VEGF levels were increased markedly in patients with PDR. VEGF concentrations in vitreous and plasma were decreased significantly after IVB into PDR eyes, and the effect lasted from 4.4 ± 2.2 days to 34.8 ± 33.7 days after injection.

Different responses of circulating endothelial progenitor cells and VEGF-plasma concentrations to low-dose metronomic and conventional chemotherapy

14053 Background: Endothelial progenitor cells (EPCs) may participate in tumor angiogenesis by providing cellular supply. This is a study that compares the effects of two conventional combination chemotherapy schedules to low-dose metronomic trofosfamide (an oral derivate of cyclophosphamide), using the number of circulating EPCs and vascular endothelial growth factor (VEGF) plasma levels in cancer patients. Methods: We measured circulating EPC and VEGF levels in 24 patients that received conventional chemotherapy for either breast cancer in an adjuvant setting or malignant lymphoma, and in 18 patients receiving metronomic chemotherapy with or without celecoxib for advanced cancer. Blood samples were obtained three times: before starting chemotherapy, 10 and 21 days after starting chemotherapy. Peripheral blood EPC levels were determined by fluorescence flow cytometry and defined by CD34- and VEGF-R2-positivity. VEGF plasma concentration was determined by ELISA. Results: The number of circulating EPCs showed a two-fold increase 21 days after conventional chemotherapy but a significant decrease under metronomic chemotherapy. VEGF-plasma-concentrations remained stable in patients under metronomic chemotherapy but significantly increased under conventional chemotherapy.This increase in VEGF plasma levels occurred even in patients that received chemotherapy in an adjuvant setting in supposed absence of tumor. Conclusions: Low-dose metronomic trofosfamide significantly decreased circulating EPCs while conventional chemotherapy increased both the number of circulating EPC and VEGF-concentrations. The increase of VEGF even in an adjuvant setting of chemotherapy without the presence of a tumor may be caused by chemotherapy-induced endothelial cell destruction. Metronomic scheduling of certain cytotoxic drugs may thus prevent tumor progression by inhibiting both tumor cell proliferation and angiogenesis. No significant financial relationships to disclose.

The relationship between plasma vascular endothelial growth factor and plasma insulin like Growth factor-i levels on diabetic nephropathy in Patients with type 2 diabetes

Plasma Vascular endothelial growth factors (p VEGFs) as well as plasma insulin like growth factors- I (pIGFs- I) has been implicated in the pathogenesis of diabetes mellitus. This study was performed to determine whether alternations of p VEGFs and pIGFs are related to diabetic nephropathy in type 2 diabetic patients.Patients & Methods:We examined the association of pVEGFs and pIGFs concentrations with fasting glucose levels, glycosylated hemoglobin (HbA1c %), urinary measured renal parameters i.e. creatinine clearance and albuminuria in 75 patients with type 2 diabetes and 25 healthy controls. Study subjects were divided into four groups using urinary albumin-to-creatinine ratio (ACR). Results:We confirmed that (i) both pVEGFs and pIGFs showed remarkable increase in all diabetic groups with worsen A/Cr ratio, as compared with controls. (ii) p VEGFs and pIGFs were increased in diabetic patients as long as glycemic control was not achieved. (iii) Vascular endothelial growth factor in plasma as well as plasma insulin like growth factors elevations were also revealed statistically. (iv) Direct positive correlation between pVEGFs and pIGFs-I with glycemic control index, albuminuria were noticed. Conclusion:The release of both p VEGFs as well as pIGFs was increased during the earlier stage of diabetic nephropathy and were significantly correlated with urinary albumin excretion. This suggested that pVEGFs could be used as an early sensitive marker for the diagnosis before the stage of microalbuminuria. and for predicting disease progression to start therapy very early.

Vascular endothelial growth factor (VEGF-A) plasma levels in non-small cell lung cancer: relationship with coagulation and platelet activation markers

SummaryPlatelet activation, commonly found in lung cancer patients, may cause the release of angiogenic factors, such as vascular endothelial growth factor (VEGF-A). The present study was designed to investigate whether plasma VEGF-A levels were associated to different stages of non-small cell lung cancer (NSCLC). Moreover, sP-selectin, prothrombin fragment 1+2 (F1+2),thrombin-antithrombin III complex (TATc) and D-dimer levels were measured to test the hypothesis of an involvement of platelet and coagulation activation in tumor angiogenesis. VEGF-A, sP-selectin, F1+2, TATc and D-dimer levels were elevated in 65 patients with NSCLC, particularly in metastatic patients. sP-selectin (p &lt;0.003) and F1+2 (p &lt;0.005) levels were independently associated to VEGF-A. In addition, patients with positive levels of both sP-selectin and F1+2 had the highest levels of VEGF-A. In conclusion, our findings support the hypothesis that thrombin generation might induce platelet activation and VEGF-A release in NSCLC.

Vascular Endothelial Growth Factor in Plasma of Patients Undergoing Peripheral Angioplasty

Vascular Endothelial Growth Factor in Plasma of Patients Undergoing Peripheral Angioplasty -

Oxidative Stress and Increase of Vascular Endothelial Growth Factor in Plasma of Patients with Peripheral Arterial Occlusive Disease

Oxidative Stress and Increase of Vascular Endothelial Growth Factor in Plasma of Patients with Peripheral Arterial Occlusive Disease -