Plasma Vascular Endothelial Growth Factor Levels Research Articles

A longitudinal study of circulating angiogenic and antiangiogenic factors and AT1-AA levels in preeclampsia

Our earlier studies of preeclampsia (PE) at delivery have demonstrated the alteration of one carbon cycle, reduced placental omega 3 fatty acids, altered circulating levels of angiogenic factors and differential placental gene-specific methylation patterns of angiogenic factors. This study was undertaken to examine changes in the levels of angiogenic factors and angiotensin II type 1 receptor autoantibodies (AT1-AAs) throughout gestation, from early pregnancy until delivery, in women with PE and to examine their association with cord angiogenic factors, blood pressure and infant weight. A total of 81 pregnant women (46 normotensive and 35 with PE) were followed at three different time points during pregnancy: 16-20 weeks (T1), 26-30 weeks (T2) and at the time of delivery (T3). The plasma levels of angiogenic factors and AT1-AAs were determined in the maternal and cord plasma by commercial enzyme-linked immunosorbent assay kits. Maternal plasma levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were lower (P<0.05 for both), whereas soluble fms-like tyrosine kinase-1 (sFlt-1; P<0.05) and the sFlt-1/PlGF ratio (P<0.01) were higher in early pregnancy in the PE group. Maternal plasma AT1-AA levels were higher (P<0.05) at T2 in women with PE. Cord plasma VEGF and soluble kinase insert domain receptor (sKDR) levels were lower (P<0.01 and P<0.05, respectively), whereas AT1-AA levels were higher (P<0.05) in the PE group. Maternal plasma VEGF levels in early pregnancy were positively associated with systolic blood pressure, whereas the sFlt-1/PlGF ratio at T2 was negatively associated with infant weight in the PE group. Low levels of proangiogenic factors (VEGF and PlGF) and high levels of AT1-AAs and antiangiogenic factors (sFlt-1 and sFlt-1/PlGF ratio) are present in the maternal circulation during early gestation in women with PE.

0136: Increased intracardiac VEGF and VWF levels revealed low grade inflammatory process and progressive endothelial damage in patients with AF

Endothelial dysfunction seems to play a pivotal role in atrial fibrillation (AF). The purpose of this study was to investigate the relationship between AF and vascular endothelial growth factor (VEGF) and to investigate the effect of different clinical forms of AF on plasma concentration of Von Willebrand Factor (vWF) at different levels of circulatory tree, both intracardiac and extracardiac. Peripheral (Pf), left atrial (LA), and coronary sinus (CS) blood samples were obtained during cardiac catheterization from 52 patients with paroxysmal AF (PAF), 36 with persistent AF (PsAF), and 17 control subjects (Ct) with Wolff-Parkinson-White syndrome. Plasma levels of VEGF and vWF were measured at the three sampled sites. Peripheral VEGF levels were higher in both PAF and PsAF patients than in controls (P≤0.03). Left atrial VEGF levels were higher in paroxysmal AF (P=0.05), but not in persistent AF (P=0.32), compared with controls. Coronary sinus and pulmonary vein VEGF levels did not differ significantly among groups. Compared with Ct, patients with PAF had higher LA plasma levels of vWF (P=0.004), but similar Pf and CS levels (both P>0.30). In contrast, patients with PsAF had higher plasma concentrations of vWF in Pf (P=0.04), LA (P<0.001), and CS (P=0.04) samples compared with Ct. Left atrial plasma concentrations of vWF in patients with PsAF were also higher than in the PAF group (P=0.04). This study suggests that inflammatory process in AF is of low grade. The heart itself is the most likely source of high left atrial VEGF; however, this disorder appears to be a transient event in AF history. AF patients presented significantly higher plasma concentrations of vWF. This study suggests an association between the clinical evolution of AF and the progression of endothelial dysfunction. Further studies will have to establish the exact mechanisms that link endothelial dysfunction and stroke in the context of AF. Abstract 0136 – Figure: vWF and VEGF plasma levels in the 3 study groups

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.

Circulating pro‐ and anti‐angiogenic mediators in patients infected with hepatitis C at different stages of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization. The objective of the current study was to determine circulating proangiogenic [vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and tumor necrosis factor (TNF-α)] and antiangiogenic [IL-4, IL-12, interferon gamma-induced protein 10 (IP-10), and angiostatin] factors in Egyptian patients with different stages of HCC. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of these mediators in plasma of 135 HCC patients (57 Child-Pugh A, 24 Child-Pugh B, and 54 Child-Pugh C stage) and 50 healthy subjects. Results showed a significant increase in plasma levels of VEGF (P < 0.001), PDGF (P < 0.001), TNF-α (P < 0.01), angiostatin (P < 0.01), and IP-10 (P < 0.001) and a significant reduction in IL-12 (P < 0.001) in HCC patients in relation to normal controls. Classifying HCC patients based on their Child-Pugh's score revealed that the maximum production of proangiogenic mediators (VEGF and TNF-α) was present in HCC patients with Child-Pugh C score which coincides with maximum reduction in antiangiogenic mediators (IL-4, IL-12, and angiostatin). Taken together, these results indicated that the determination of these factors in different Child-Pugh's scores of HCC might be an important guide in clinical decision making regarding therapy and outcome.

Vascular endothelial growth factor and amyotrophic lateral sclerosis: The interplay with exercise and noninvasive ventilation

We evaluated plasma vascular endothelial growth factor (VEGF) levels in patients with amyotrophic lateral sclerosis (ALS) with reference to the effects of respiratory failure, noninvasive ventilation (NIV), and exercise. We studied plasma VEGF levels in 83 ALS patients, 20 healthy controls, and 10 patients with other disorders. There were 4 groups of ALS patients: G1, 27 patients without respiratory problems; G2, 14 patients stabilized on nocturnal NIV; G3, 30 patients presenting with respiratory failure; G4, 12 patients on an aerobic exercise protocol. VEGF plasma levels did not differ significantly between ALS patients and controls, or between ALS groups. In G3, the mean VEGF levels increased 75% during NIV. In G4, the mean VEGF level increased by 300% during the exercise program. VEGF levels did not change during the course of the disease. VEGF levels in ALS depend on changes in ventilation and exercise but are probably not affected by the disease process itself.

One Possible Mechanism of Pulsed Dye Laser Treatment on Infantile Hemangioma: Induction of Endothelial Apoptosis and Serum vascular endothelial growth factor (VEGF) Level Changes.

Pulsed dye laser (PDL) is an important treatment for superficial infantile hemangioma, but few studies report on its cellular mechanism. The aim of this study was to evaluate alterations of serum vascular endothelial growth factor (VEGF) level in infantile hemangioma (IH) patients after laser treatment and effects of PDL irradiation on human umbilical vein endothelial cells (HUVECs) in vitro, as well as to explore the biomolecular mechanisms and ultrastructure changes of the PDL effect. 74 children with infant hemangioma including 45 patients in proliferating phase, 18 patients in involuting phase, 11 patients in involuted phase and 10 healthy children were engaged in this study. The plasma VEGF levels of children were measured with the enzymelinked immunosorbent assay (ELISA). 24 hours after, HUVECs cultured in vitro were irradiated with PDL, cell apoptosis, mRNA levels of VEGF, and changes of ultrastructure were evaluated using flow cytometry, real-time reverse transcriptase polymerase chain reaction (RT-PCR), and transmission electron microscopy, respectively. The serum VEGF concentrations in children with proliferating hemangiomas were significantly higher than in patients with involuting / involved hemangiomas and healthy patients. After receiving 3 laser treatments, the plasma VEGF levels of IH patients in proliferating hemangiomas decreased significantly. PDL irradiation could down-regulate VEGF mRNA expression of HUVECs, and increase cell apoptosis rate. The present study demonstrates that PDL irradiation imparts apoptosis induction effects on HUVECs in vitro. Furthermore, our results suggest that vascular endothelial growth factor may be of particular importance in pathophysiology and PDL treatment of hemangiomas, also serum VEGF levels may be used as an aid in the follow up of IH. This provides valuable evidence of the PDL effect on infantile hemangioma.

Effect of oxytocin treatment on explant size, plasma and peritoneal levels of MCP-1, VEGF, TNF-α and histopathological parameters in a rat endometriosis model

ObjectiveTo determine the effects of oxytocin (OT) on surgically induced endometriosis in a rat model. Study designTwelve female Sprague-Dawley rats were included. After the implantation and establishment of autologous endometrium onto the abdominal wall peritoneum, the rats were randomly divided into two groups, treated with intramuscular oxytocin (OT group, 160μgkg/day, n=6) or isotonic NaCl solution (control group, 1mLkg/day, n=6) for 28 days. To evaluate the therapeutic effects of OT, the explant volumes were calculated and the levels of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1, and TNF-α were measured in plasma and peritoneal fluid. Endometriotic explants were examined histologically by semiquantitative analysis. ResultsAfter treatment, the mean endometriotic explant volume was decreased in the OT group (p=0.016). The histopathological score and VEGF immunoexpression of endometriotic explants were significantly lower in the OT group (p=0.007) than in controls (p=0.000). Inflammatory cytokine levels in plasma and peritoneal fluid were considerably decreased in the OT group. Moreover, TUNEL immunohistochemistry clearly demonstrated more apoptotic changes in the mononuclear cells of the OT group compared with controls. ConclusionWe suggest that oxytocin might be considered as a potential candidate therapeutic agent for endometriosis.

VEGF levels in diagnosis of vasculitic neuropathy.

Vascular endothelial growth factor (VEGF) is secreted from endothelial cells and pericytes in response to hypoxia. It induces angiogenesis and microvascular hyperpermeability. We observe serum VEGF concentrations in some patients with vasculitic neuropathy. Plasma VEGF was measured using GenWay's human VEGF ELISA Kit, which is based on standard sandwich enzyme-linked immune-sorbent assay technology. Human VEGF specific-specific monoclonal antibodies are precoated onto 96-well plates. The human specific detection polyclonal antibodies are biotinylated. The test samples and biotinylated detection antibodies were added to the wells subsequently and then followed by washing with PBS or TBS buffer. Avidin-Biotin-Peroxidase Complex was added and unbound conjugates were washed away with PBS or TBS buffer. HRP substrate TMB was used to visualize HRP enzymatic reaction. The VEGF levels were measured in 5 patients with vasculitic neuropathy and 8 healthy controls. Plasma VEGF was higher in subjects with vasculitic neuropathy as compared to controls. In the control group, we obtained VEGF levels from 9.8 pg/mL up to 15 pg/mL with an average of 11.6 pg/mL for males and 8.9 pg/mL up to 14.5 pg/mL with average of 11.2 pg/mL for females. In female patients with vasculitic neuropathy the plasma VEGF levels were between 79.9 pg/mL and 111.2 pg/mL, with an average of 92.375 pg/mL. We had one case with vasculitic neuropathy in men, in which the plasma VEGF level was 102.9 pg/mL. The results from our study indicate that plasma VEGF levels are significantly associated with vasculitic neuropathy and may be used to predict this disease.

Association of vascular endothelial growth factor single nucleotide polymorphisms on the prognosis of breast cancer patients

Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of breast cancer. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to breast cancer. A total of 200 patients with histologically confirmed cases of breast cancer and 200 healthy women were genotyped for VEGF single nucleotide polymorphisms (405G > C and -1154G > A) by polymerase chain reaction-restriction fragment length polymorphism analysis. Pre-operative plasma VEGF levels were determined by enzyme-linked immunosorbent assay in 200 women with breast cancer and in 200 normal female controls. The genotype frequencies of the +405G > C, -1154G > A polymorphisms did not show a significant deviation from the Hardy-Weinberg expectation. The minor allele frequencies of the +405G > C and -1154G > A polymorphisms among cases and controls were 33.5% (C allele), 31.5% (A allele) and 35% (C allele), 34.5% (A allele) respectively. +405GG and -1154GG genotypes were associated with higher levels of VEGF among breast cancer cases and controls. Increased plasma VEGF levels were significantly associated with, clinical stage of the disease (P = 0.035). Although none of the polymorphisms were significantly associated with breast cancer, some of the VEGF genotypes may influence tumor growth through an altered expression of VEGF and tumor angiogenesis.

Relationship between plasma vascular endothelial growth factor and tumor necrosis factor-alpha and obstructive sleep apnea hypopnea syndrome in children

To investigate the relation of plasma vascular endothelial growth factor(VEGF) and tumor necrosis factor-α (TNF-α) with obstructive sleep apnea-hypopnea syndrome(OSAHS) in children. Eighty children were recruited from October 2008 to March 2009, including 60 children with snoring and 20 healthy children without snoring as control. Plasma VEGF or TNF-α concentration was measured by enzyme-linked immunosorbent assay (ELISA) respectively. Sixty children with snoring underwent an overnight polysomnography test their PSG data, including whole night mean saturation (MSaO2), lowest oxygen saturation (LSaO2), desaturation cumulate time/total sleep time (DCT/TST), oxygen desaturation index 3 (ODI3), apnea-hypopnea index (AHI), obstructive apnea index (OAI), were collected and analysed. SPSS 13.0 software was used to analyze the data. The levels of plasma VEGF and TNF-α in children with OSAHS(540.45 pg/ml and 311.94 pg/ml) were higher than those in children with snoring alone (234.45 pg/ml and 97.55 pg/ml) or those in healthy children (259.80 pg/ml and 120.70 pg/ml), with statistically significant differences(HC value:14.176 and 15.571, P < 0.05, respectively), but with no statistical difference between children with snoring alone and healthy children (P > 0.05). The differences in plasma VEGF or TNF-α levels between children with moderate and severe hypoxemia and children with mild hypoxemia were not statistically significant (P > 0.05). Spearman rank correlation analysis showed no significant correlation between plasma level of VEGF or TNF-α and LSaO2, MSaO2, ODI3, DCT/TST, OAI, AHI or BMI (r values were <0.5, P > 0.05). Plasma levels of VEGF and TNF-α increase in children with OSAHS.

Plasma levels of osteopontin and vascular endothelial growth factor in association with clinical features and parameters of tumor burden in patients with multiple myeloma.

The aim of this pilot study was to determine the plasma levels of osteopontin (OPN) and vascular endothelial growth factor (VEGF) and find possible association between them and main clinical features and parameters of tumor burden in patient with multiple myeloma (MM). Plasma levels of OPN and VEGF were determined in 44 newly diagnosed MM patients and 24 healthy persons by ELISA method. These values were compared with the presence of anemia, renal dysfunction, and bone lesions as myeloma related clinical manifestations and with serum beta-2 microglobulin and Durie-Salmon clinical stage as prognosticators related to tumor mass. The value of OPN was significantly higher in MM patients with evident bone lesions (P = 0.03) and there was also a positive correlation with serum beta-2 microglobulin (r = 0.366; P = 0.04). Furthermore, patients with lower Durie-Salmon stage had significantly lower OPN and VEGF levels (P = 0.05; P = 0.04, resp.). Our preliminary results found positive association between plasma level of OPN, tumor burden, and bone destruction. Further analysis should provide information about the possible use of OPN as useful clinical biomarker for monitoring bone disease and tumor mass, as well as a prognostic factor, or a possible target for pharmacological intervention.

Supplemental Oxygen Reverses Hypoxia-induced Smooth Muscle Cell Proliferation by Modulating HIF-alpha and VEGF Levels in a Rabbit Arteriovenous Fistula Model

Numerous mechanisms for the formation of intimal hyperplasia have been proposed but none have been proven or accepted. Our research focuses on the potential role of hypoxia-inducible factors (HIFs), vascular endothelial growth factor (VEGF), and platelet-derived growth factors as well as the extracellular signal-regulated kinase (ERK), phosphatidylinositide 3-kinase /protein Kinase B (PI3-K/AKT) pathway in hypoxia-mediated intimal hyperplasia processes. We hypothesize that HIF and VEGF will be downregulated with supplemental oxygen in our arteriovenous fistula rabbit model. Rabbits were randomized into different experimental groups with varying oxygen exposure (21% O2 or 30% O2) and receipt of surgery (surgery with fistula formation, no surgery, or sham operation with skin incision only). Plasma samples were collected at designated intervals in which cytokines and smooth muscle cell proliferation were measured. In addition, cell specimens were exposed to hyperoxic, normoxic, and hypoxic environments with cytokines measured at various time points. Placement of an arteriovenous fistula resulted in hypoxia-induced HIF stabilization with a concurrent increase in VEGF levels. There was a 4.2-fold induction in HIF-1α levels in animals that were placed in normal air after surgery when compared with animals that were exposed to hyperoxic air. Also, VEGF level significantly increased after surgery in the normoxic group, reaching a maximum of 959 pg/mL. Plasma VEGF levels in the surgery and supplemental oxygen group were significantly lower than the normoxic surgery group with almost a 45% reduction in plasma VEGF levels (524 pg/mL). Activation of VEGF receptors on smooth muscle cells through ERK1 and AKT pathways resulted in significant smooth muscle cell proliferation and migration. These effects are dramatically reduced in animals that are exposed to a hyperoxic environment of 30% oxygen. Our results suggest that short-term administration of supplemental oxygen inhibits HIFs and VEGF signaling to reduce smooth muscle proliferation in the local blood vessel. These results provide strong support for the therapeutic use of supplemental oxygen after arterial surgery to reduce intimal hyperplasia. These findings also provide a nidus for future clinical trials to determine whether this is clinically applicable in humans.

Relationship of plasma and synovial fluid vascular endothelial growth factor with radiographic severity in primary knee osteoarthritis

Recent evidence suggests that angiogenesis and inflammation contribute to the development and progression of osteoarthritis (OA). The purpose of this study was to investigate vascular endothelial growth factor (VEGF) levels in plasma and synovial fluid of patients with knee OA and to determine the relationship of VEGF levels with disease severity in knee OA. A total of 100 subjects were enrolled in this study (80 knee OA patients and 20 healthy controls). Plasma and synovial fluid VEGF levels were analysed using enzyme-linked immunosorbent assay. VEGF expressions in synovial membrane and articular cartilage samples were assessed using immunohistochemistry. VEGF level in synovial fluid of knee OA patients was tenfold higher than that in paired plasma (P < 0.001). Both plasma and synovial fluid VEGF exhibited a positive correlation with radiographic severity (r = 0.454 and r = 0.727, P < 0.001, respectively). VEGF expression was highly detectable in synovial lining cells and articular chondrocytes of knee OA patients. VEGF levels in both plasma and synovial fluid were positively correlated with the severity of knee OA. Therefore, VEGF may be useful for monitoring OA severity and could play a substantial role in the development and progression of knee OA.

Angiogenesis is increased in advanced haemophilic joint disease and characterised by normal pericyte coverage

Repeated intra-articular bleedings in patients with haemophilia results in a crippling arthropathy for which no specific treatment is currently available. Recent studies have shown that neoangiogenesis is involved in the pathologic process. The aim of this study was to determine whether angiogenesis is dysregulated in haemophilic joint disease (HJD). Synovial tissue and synovial fluid were collected from patients with severe haemophilia undergoing knee or hip replacement and from a control group consisting of non-haemophilic patients undergoing diagnostic procedures. In a second set of patients, blood samples were collected in patients with mild, moderate and severe haemophilia A when free from current bleeding. Analysis of microvascular density, vascular endothelial growth factor (VEGF) expression and pericyte coverage was performed by immunofluorescence. Analyses of VEGF concentrations in plasma, platelet lysates and synovial fluid were performed by ELISA. Microvascular density and VEGF expression were significantly increased in synovial tissue from haemophilic patients compared with controls (P=0.005 and P=0.02, respectively). There was no difference in pericyte coverage of synovial vessels or levels of VEGF in plasma, platelet lysates or synovial fluid. Angiogenesis observed as synovial microvascular density, and VEGF expression is increased in HJD. As pericyte coverage was similar in synovial vessels from haemophilic and non-haemophilic patients, we assume that the vessels were mature, suggesting that the rate of new vessel formation is low in the chronic phase of haemophilic joint disease.

Treatment with Huisheng oral solution inhibits the development of pulmonary thromboembolism and metastasis in mice with Lewis lung carcinoma

The aim of this study was to investigate whether Huisheng oral solution (HSOS) has an inhibitory effect on the development of pulmonary thrombosis and metastasis in mice with Lewis lung carcinoma (LLC), and to explore the possible mechanisms involved. A mouse model of LLC was developed, and model mice were divided into either a treatment group or a control group to undergo treatment with HSOS or normal saline. Normal mice treated with saline were used as normal controls. On day 25 after treatment, blood samples were drawn from the eyes of half the mice in each group to determine blood cell counts and plasma levels of D-Dimer and vascular endothelial growth factor (VEGF), while heart blood samples were collected from the remaining mice to measure the rate of thrombin-induced platelet aggregation. For all mice, pathological analyses of the cerebrum, lung, mesentery, femoral vein, external iliac vein and spleen were performed. Tumors were weighed to assess the impact of HSOS treatment on tumor growth, and the number of thrombi, metastatic nodules and neovessels in the tumor tissue were counted. In addition, 24 normal New Zealand rabbits were divided into two groups and treated with either HSOS or normal saline to determine the rates of ADP-, collagen- or thrombin-induced platelet aggregation. Compared with the model group, HSOS treatment decreased the incidence of pulmonary thromboembolism and metastasis, the number of metastatic nodules, the plasma levels of D-dimer and VEGF, the rate of collagen-induced platelet aggregation in rabbits and the numbers of leukocytes and tumor neovessels (P<0.05 for all). It increased the thymus and spleen coefficients and the number of platelets (P<0.05 for all), but had no significant effect on thrombin-induced platelet aggregation in mice and rabbits, ADP-induced platelet aggregation in rabbits, or the number of red blood cells. The reduced rate of tumor growth was 9.7% in mice treated with HSOS. HSOS treatment effectively reduced the development of pulmonary thromboembolism and metastasis in mice bearing LLC via mechanisms possibly associated with ameliorating a blood hypercoagulable state, decreasing tumor angiogenesis and enhancing immunity.

VEGFA variants are associated with pre-school lung function, but not neonatal lung function

Vascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood. We analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort. Asthma was diagnosed prospectively, and lung function measurements were obtained at birth and 6years of age. Plasma VEGF levels were measured at 18months of age. We used a Bonferroni adjusted significance level. Findings were replicated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort at age 8. At age six, three SNPs from the same linkage block were associated with FEV1 (rs699947, P=1.31E-05), independent of asthma, and there were suggestive associations between FEV1/FVC ratio and rs833052 and maximal mid-expiratory flow and rs6900017. Replication in the PIAMA cohort showed borderline association between FEV1 and rs699947 and significant meta-analysis result. SNPs upstream and nearby rs699947 were nominally associated with VEGF plasma levels. VEGF levels were not associated with asthmatic symptoms or lung function measures. VEGF gene variants are associated with lung function at school age, but not at birth, suggesting a role of VEGF in post-natal lung function development.

Selective inhibition of PKCβ2 preserves cardiac function after myocardial infarction and is associated with improved angiogenesis of ischemic myocardium in diabetic rats

Activation of PKCβ2 induced by hyperglycemia contributes to impaired angiogenesis in endothelial cells. The purpose of the present study was to investigate whether PKCβ2 inhibition can attenuate the hyperglycemia-induced impaired angiogenesis of myocardium to improve cardiac function following myocardial infarction (MI) in diabetes. In vitro, human umbilical vein endothelial cells (HUVECs) were cultured in low glucose (L-G) (5.6 mmol/l) or high glucose (H-G) (33.3 mmol/l) medium in the presence or absence of LY333531 (LY333) (10 nmol/l), a selective PKCβ2 inhibitor. In vivo, with the use of an MI diabetic rat model, animals were randomized to receive LY333 (10 mg/kg/day) orally for 4 weeks after MI, or no treatment whatsoever. Treatment of HUVECs with LY333 prevented the H-G-induced decrease of tube formation, migration and proliferation. Furthermore, exposure of HUVECs to H-G activated PKCβ2 and decreased levels of phospho-Akt (p-Akt) and phospho-endothelial nitric oxide synthase (p-eNOS) expression, which was also prevented by LY333. Compared with MI rats without therapy, LY333-treated MI rats showed an increase in left ventricular ejection fraction (LVEF) and fractional shortening (FS), but a reduction in infarct size. Furthermore, treatment of rats with LY333 not only significantly increased the capillary density of ischemic myocardium, but also significantly elevated the levels of p-Akt and p-eNOS expression. We also observed a significant increase of VEGF expression in myocardium measured by immunostaining in MI and LY333 groups compared to sham group. Anti-CD31 immunostaining revealed that MI rats treated with LY333 exhibited increased density of capillaries compared with sham group rats. However, treatment of rats with LY333 did not result in significant increases in vascular endothelial growth factor (VEGF) expression at both the mRNA and protein levels in myocardium, and in the plasma level of VEGF compared with MI rats without therapy. Overall, these results suggest that inhibition of PKCβ2 may be a novel therapeutic approach for preserving cardiac function after MI, in part by improving impaired angiogenesis of myocardium in diabetes.

Phase2 study of bevacizumab with carboplatin–paclitaxel for non-small cell lung cancer with malignant pleural effusion

Vascular endothelial growth factor (VEGF) is involved in non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE), but little is known regarding the efficacy of bevacizumab (Bev) with carboplatin-paclitaxel (CP) for NSCLC with MPE. Chemotherapy-naive non-SQ NSCLC patients with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. In the first cycle, the treated patients received only CP to prevent Bev-induced wound healing delayed after chest drainage. Subsequently, they received 2-6 cycles of CP with Bev. Patients who completed more than 4 cycles of CP and Bev without disease progression or severe toxicities continued to receive Bev alone as a maintenance therapy. The primary end point was overall response, although an increase in MPE was allowed in the first cycle. The VEGF levels in plasma and MPE were measured at baseline, and the VEGF levels in plasma were measured after 3 cycles of chemotherapy. Between September 2010 and June 2012, 23 patients were enrolled. The overall response rate was 60.8%; the disease control rate was 87.0%. Sixteen patients received maintenance therapy, following a median of 3 cycles. Median progression-free and overall survival times were 7.1months (95% confidence interval [CI], 5.6-9.4months) and 11.7months (95% CI, 7.4-16.8months), respectively. Most patients experienced severe hematological toxicities, including ≥grade 3 neutropenia; none experienced severe bleeding events. The MPE control rate improved on combining CP with Bev (CP, 78.3%; CP with Bev, 91.3%; P=0.08). The median baseline VEGF level in MPE was 1798.6 (range 223.4-35,633.4) pg/mL. Plasma VEGF levels significantly decreased after 3 chemotherapy cycles (baseline, 513.6±326.4pg/mL, post-chemotherapy, 25.1±14.1pg/mL, P<0.01). CP plus Bev was effective and tolerable in chemotherapy-naïve non-squamous NSCLC patients with MPE.

The Chemokine Stromal Cell–Derived Factor-1α Promotes Endothelial Progenitor Cell–Mediated Neovascularization of Human Transplanted Fat Tissue in Diabetic Immunocompromised Mice

Stromal cell-derived factor-1α is a chemokine and mediates endothelial progenitor cell-induced neovascularization. Because vascularization of a graft is crucial for its survival, the authors investigated whether stromal cell-derived factor-1α could improve fat graft survival by inducing endothelial progenitor cell-mediated neovascularization and preventing its resorption. The authors injected 1 ml of human fat tissue into the scalps of 30 diabetic and 10 nondiabetic immunocompromised mice. The fat grafts were treated with phosphate-buffered saline or stromal cell-derived factor-1α. Determination of graft phenotype included measurements of their weights and volumes, vascular endothelial growth factor (VEGF) levels, the stromal cell-derived factor-1α receptor CXCR4, VEGF receptor 2, endothelial nitric oxide synthase, serine/threonine-specific protein kinase (protein kinase B), caspase 3, and cytochrome c expression levels, and the extent of vascularization. Eighteen days after transplantation, stromal cell-derived factor-1α treatment of the grafts in the diabetic mice (1) increased plasma VEGF levels; (2) raised VEGF receptor 2, CXCR4, endothelial nitric oxide synthase, and protein kinase B expression levels; and (3) reduced caspase 3 and cytochrome c expression levels in the fat grafts. Fifteen weeks after transplantation, stromal cell-derived factor-1α treatment of the grafts prevented their resorption and increased the extent of their vascularization. Locally delivered stromal cell-derived factor-1α increases fat graft survival by stimulating neovascularization and reducing fat cell apoptosis through an endothelial progenitor cell-mediated mechanism.

VEGF plasma level variations in duloxetine-treated patients with major depression

BackgroundThe vascular endothelial growth factor (VEGF) signaling, which modulates angiogenesis and neurogenesis within the neurovascular unit, might play an important role in the neuro-endocrine-immune (NEI) stress-adaptation system. Recent evidence suggests that VEGF is involved in the pathophysiology of a number of diseases including major depressive disorder (MDD) and is affected by some treatments, including antidepressants. The objective of the study was to investigate the VEGF level variations in MDD patients during antidepressant treatment with duloxetine, a relatively new SNRI. MethodsA total of 30 MDD patients and 32 healthy controls were assessed using the Hamilton Depression Scale (HAM-D) and monitored for VEGF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60mg/day) and at baseline, respectively. ResultsAccording to early clinical response to duloxetine (defined at week 6 by reduction>50% of baseline HAM-D score), the MDD patients were divided into early responders (ER) and early non-responders (ENR). During duloxetine treatment, we found an opposite trend in the VEGF levels between ER and ENR: in ER the VEGF levels significantly increased in association with clinical response at W6, while in ENR the VEGF levels significantly decreased in association with an overall clinical response at W12. LimitationsSmall sample size. ConclusionsThe opposite trends in VEGF levels, increasing in ER and decreasing in ENR, might reflect differential Norepinephrine/Serotonin effects of duloxetine on differential neurobiological backgrounds of depressive syndromes. Overall, the modulation of VEGF signaling within the neurovascular unit during antidepressant treatment could hypothetically favor the remodeling of neural circuitry, contributing to adaptive adjustment of the NEI stress-adaptation system.