vegfa - vascular endothelial growth factor A
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Pubmed
Journal: Transplantation proceedings
February/25/2015
Abstract
OBJECTIVE
The aim of this work was to investigate single-nucleotide polymorphisms (SNPs) in multiple genes on chromosome 6p in corneal transplant recipients known to be at increased risk of failure through immunologic rejection (ie, "high-risk" corneal transplants). Tumor necrosis factor alpha (TNF-α) is a key immunoregulatory cytokine in the ocular environment, interacting with a variety of factors in a synergistic way and playing a crucial role in many stages of the inflammatory response. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors, supporting both hemangiogenesis and lymphangiogenesis, both key in transplant tolerance and rejection. Interleukin-17 (IL-17) is a multifunctional cytokine produced by T-helper 17 cells, exerting specific effector functions during an immune response. Association of SNPs in all 3 genes with corneal transplant outcome was therefore investigated.
METHODS
Three hundred five corneal transplant recipients were followed for 3 years, and episodes of allograft rejection were recorded. With the use of patient DNA, 6 SNPs of 3 different genes on chromosome 6p were investigated. The TNF-α promoter SNP -308 G/A (rs1800629) was analyzed with the use of induced heteroduplex generation; 2 VEGF-A functional variants were analyzed, -2578 (rs699947) C/A and -1154 (rs1570360) G/A, with the use of Taqman genotyping assays; and 3 nonsynonymous IL-17F SNPs in exon 3 (negative strand), (rs2397084) A/G, (rs11465553) G/A, and (rs763780) A/G, were investigated with the use of direct sequencing. Haplotypes were inferred with the use of PHASE using positive strand alleles, and exact measures of association were determined with the use of Mid-P exact chi-square.
RESULTS
Six common haplotypes were inferred, with the haplotype TNF-α (rs1800629), VEGF-A (rs699947), (rs1570360), IL-17F (rs763780), (rs11465553), and (rs2397084) ACGTCT having a significant association with corneal transplant rejection (odds ratio, 1.78; 95% confidence interval, 1.01-3.11; P = .04).
CONCLUSIONS
The results suggest that patients carrying a combination of SNPs for TNF-α, VEGF-A, and IL-17F of ACGTCT haplotype may have an increased risk of corneal allograft rejection compared with patients carrying other haplotypes.
Pubmed
Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
May/3/2007
Abstract
OBJECTIVE
Vascular endothelial growth factor (VEGF), an important regulator of angiogenesis and vascular permeability, is involved in various steps of ovarian carcinogenesis. Gene polymorphisms within the gene encoding VEGF were shown to be independently associated with an adverse outcome in various malignancies. No data are available for ovarian cancer.
METHODS
In the present multicenter study, we examined three common polymorphisms within the VEGF gene (-634G/C, -1154G/A, and -2578C/A) known to be associated with an increased VEGF production in 563 Caucasian patients with ovarian cancer from Austria and Germany using pyrosequencing. Results were correlated with clinical data.
RESULTS
The three investigated polymorphisms did not correlate with any of the investigated clinicopathologic variables. In univariate and multivariate models, no significant correlations between any polymorphism and patients' overall survival were ascertained. Simultaneous carriage of the three homozygous genotypes (i.e., VEGF -634C/C, VEGF -1154G/G, VEGF -2578C/C) known to be associated with increased VEGF expression in an individual patient, however, was independently associated with a shortened overall survival (hazard ratio, 2.1; 95% confidence interval, 1.1-3.9; P=0.02).
CONCLUSIONS
We present the first data on VEGF gene polymorphisms in ovarian cancer. Simultaneous carriage of the three investigated homozygous genotypes was shown to be an independent adverse prognosticator of overall survival.
Pubmed
Journal: The international journal of neuropsychopharmacology
March/29/2015
Abstract
Recent studies suggest that the angiogenic cytokine vascular endothelial growth factor (VEGF) is involved in the pathogenesis of depression. However, only a few studies have investigated serum VEGF levels in individuals with depression, or the possible association between genetic variants within the VEGF gene and depression. The purpose of the present study was to investigate differences between serum VEGF levels in individuals with depression vs. control individuals, and associations between genetic markers located within VEGF and depression. In addition, determinants of the serum VEGF levels were identified. One-hundred and fifty-five depressed subjects and 280 controls were included in the study. All individuals returned a questionnaire and participated in a semi-structured diagnostic interview. Eleven single nucleotide polymorphisms were successfully analysed. VEGF levels were measured in serum by immunoassay and independent determinants of the serum VEGF level were assessed by generalized linear models.The main findings were that depression, severity of depression, previous depressive episodes, age and body mass index (BMI) were associated with higher serum VEGF levels. The genetic marker rs10434 was significantly associated with depression after correction for multiple testing, but not with the serum VEGF level. Our final model included depression and BMI as predictors of serum VEGF levels. Our study suggests a role for circulating serum VEGF in depression. Furthermore, our data also demonstrate that other factors than a diagnosis of depression influence the serum VEGF level. The importance of these factors should be emphasized when studies are compared.
Pubmed
Journal: Zhongguo shi yan xue ye xue za zhi
October/12/2011
Abstract
This study was aimed to investigate the effects of bortezomib on VEGF gene expression of endothelial cell line HMEC-1, and to determine the changes of the transcriptional regulation activity of hypoxia-inducible factor 1 (HIF-1alpha) and expression intensity of Annexin A2, so as to analyze the possible mechanisms of the above expression of VEGF gene. Expression intensity of VEGF gene was determined by real-time quantitative PCR; the relative proliferation activity of cells was assayed by cell count kit CCK-8; the expression intensity of carbonic anhydrase IX (CA IX) gene was detected by RT-PCR; expression of Annexin A2 at gene and protein levels were determined by real-time quantitative PCR and Western blot respectively. The results showed that after being treated by bortezomib with 2.5, 5.0, 10 nmol/L for 12 hours, the expression intensity of VEGF gene of endothelial cell line HMEC-1 was as follows: 0.730 +/- 0.106, 0.673 +/- 0.153, 0.767 +/- 0.090 (as 1.0 was made in 0 nmol/L) (p < 0.05); the proliferation activity of cells was not significantly suppressed by bortezomib in 2.5, 5.0 nmol/L (p > 0.05), while that was significantly suppressed by bortezomib of 10 nmol/L (p = 0.024), The results from RT-PCR showed that expression intensity of CA IX gene was conspicuously down-regulated by bortezomib in different concentrations, which suggested that the transcriptional regulation activity of HIF-1alpha was inhibited by bortezomib. And down-regulated expression of Annexin A2 protein by bortezomib in different concentrations was confirmed by real-time quantitative PCR and Western blot. It is concluded that low doses of bortezomib has no significant inhibition effect on the activity of proteasome. Bortezomib may down-regulate the expression of VEGF gene of endothelial cell through regulating the activity of HIF-1alpha and the expression of Annexin A2.
Pubmed
Journal: Diabetes
June/7/2004
Abstract
Diabetic retinopathy and nephropathy cause significant morbidity in patients with diabetes. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor and is implicated in both of these diabetes complications. We previously reported transfection studies showing the VEGF -460 and VEGF +405 polymorphisms to increase basal VEGF promoter activity by 71% compared with the wild-type sequence. Therefore, we investigated the association of these VEGF polymorphisms with proliferative diabetic retinopathy and diabetic nephropathy. DNA was isolated from 267 U.K. Caucasians with diabetes, comprising 69 patients with proliferative retinopathy and 198 patients with other grades of retinopathy. The distribution of VEGF -460 genotype was significantly different between the proliferative retinopathy and nonproliferative retinopathy groups (P = 0.027); specifically, carriage of the VEGF -460C allele was associated with proliferative diabetic retinopathy (odds ratio 2.5 [95% CI 1.20-5.23]). The VEGF -460 genotype was predictive of retinopathy, even after controlling for blood pressure, glycemic control, duration of diabetes, and obesity (P = 0.02). The VEGF +405 genotype did not associate with proliferative retinopathy, and neither polymorphism was associated with diabetic nephropathy. The VEGF -460C polymorphism is a positive independent predictive factor for the development of proliferative diabetic retinopathy. Increased VEGF production from high-expressing haplotypes, including -460C, may promote neovascularization.
Pubmed
Journal: Journal of clinical immunology
February/24/2010
Abstract
BACKGROUND
Chlamydophila pneumoniae may contribute to the pathogenesis of asthmatic airway inflammation through chemical mediators secreted by C. pneumoniae-infected bronchial epithelial cells (BECs). Recently, CCL20 and vascular endothelial growth factor (VEGF) were reported to be released from BECs and to play a role in the pathogenesis of asthma.
OBJECTIVE
To determine if C. pneumoniae infection of BECs induces the secretion of CCL20 and VEGF, we measured that by ELISA in human BECs infected with C. pneumoniae. Transcripts of CCL20 and VEGF were assayed by semi-quantitative RT-PCR. To investigate the underlying mechanism, the activation of MAPK and intracellular reactive oxygen species (ROS) in these C. pneumoniae-infected BECs was measured, as well as the effects of inhibitors of MAPK and ROS on CCL20 and VEGF expression.
RESULTS
Compared with non-infected BECs, C. pneumoniae-infected BECs showed enhanced secretion of CCL20 and VEGF. C. pneumoniae-infected BECs also showed enhanced intracellular ROS and an increased ratio of phosphorylated to non-phosphorylated p38. Inhibition of p38 suppressed CCL20 and VEGF secretion, as did a NADPH oxidase blocker and an antioxidant, in C. pneumoniae-infected BECs.
CONCLUSIONS
C. pneumoniae infection of BECs may play a role in the pathogenesis of asthma through the enhanced production of CCL20 and VEGF. The association between increased cytokine production and increased intracellular ROS suggests that antioxidants may benefit asthmatics in selected situations.
Pubmed
Journal: Fertility and sterility
February/19/2009
Abstract
OBJECTIVE
To measure the levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) induced by thrombin in endometrial stromal cells (ESC).
METHODS
Evaluation of the effects of thrombin, thrombin receptor activator peptide 6 (TRAP-6), and D-phenylalanyl-1-propyl-L arginine chloromethyl ketone (PPACK) on the production of VEGF and MMPs by ESC.
METHODS
Research laboratory at the Oita University Medical School.
METHODS
Eight endometrial specimens in the secretory phase.
METHODS
ESC were incubated for 24 hours with thrombin, TRAP-6, and PPACK.
METHODS
The levels of VEGF, MMP-1, and active MMP-2 were measured by enzyme-linked immunosorbent assay (ELISA). The presence of protease-activated receptor-1 (PAR-1) and activation of mitogen-activated protein (MAP) kinase were detected by Western blot analysis.
RESULTS
Following stimulation by thrombin and TRP-6, the production of VEGF, MMP-1, and active MMP-2 statistically significantly increased; U0126 and PPACK statistically significantly suppressed the increases in the production of VEGF, MMP-1, and active MMP-2 induced by thrombin and TRAP-6. Activity by MAP kinase was induced by treatment with thrombin and TRAP-6 and was suppressed by PPACK.
CONCLUSIONS
The results suggest that thrombin stimulates the production of VEGF and MMPs by a mechanism involving the MAP kinase system. The increases in VEGF and MMPs may contribute to neovascularization, which promotes the proliferation of endometrium and placentation.
Pubmed
Journal: Oncology reports
March/2/2017
Abstract
Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors. VEGF165b was recently isolated as the anti-angiogenic VEGF splice variant. In the present study, we examined the association between VEGF165b expression and clinicopathological characteristics in order to determine how VEGF165b produced from oral squamous cell carcinoma (OSCC) affects the stromal cell biological activity. We examined the relationships between the expressions of both VEGF isoforms in normal human dermal fibroblasts (NHDFs) and OSCC cell lines (HSC2, 3, 4 and SAS). Our analyses indicated that both the mRNA and protein expression levels of VEGF165b in the HSC2 and SAS cells were higher than those in the NHDFs. VEGF165b did not promote cell growth or invasive capabilities, but it induced the cell adhesive capabilities to ECM. Although strong expression of the VEGF165 isoforms in tumor cells of OSCC tissues was observed, there was no significant difference in the VEGF165b expression level among the various degrees of malignancy. OSCC cells secrete VEGF165b into the stroma, and this factor may contribute to the process of anti-angiogenesis by inhibiting gelatinase-expressing cells and activating cell adhesive capabilities to ECM, such as that of fibroblasts surrounding tumor cells.
Pubmed
Journal: Molecular cancer research : MCR
July/6/2008
Abstract
Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP) regulate each other, contributing to tumor progression. We have previously reported that MMP9 induces the release of tumor VEGF, promoting ascites formation in human ovarian carcinoma xenografts. The aim of this study was to investigate whether tumor-derived VEGF regulated the expression of gelatinase by the stroma, influencing the invasive properties of ovarian tumors. Tumor variants derived from 1A9 human ovarian carcinoma, stably expressing VEGF(121) in the sense (1A9-VS-1) and antisense orientations (1A9-VAS-3), were used. In vivo, zymographic analysis of tumors from 1A9-VS-1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases, particularly murine MMP9, indicating that VEGF stimulates host expression of the matrix-degrading enzyme. Murine MMP9 expression was also high in the ovaries of mice bearing 1A9-VS-1 tumors. The effect on host MMP9 activity was organ-specific. The levels of host pro-MMP9 in ovaries correlated with the plasma levels of tumor VEGF and with the selective invasion of the ovaries. Induction of host MMP9 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice carrying both intraperitoneal and subcutaneous tumors. The anti-VEGF antibody bevacizumab (Avastin) inhibited MMP9 expression and tumor invasion in the ovaries of mice bearing 1A9-VS-1 tumors. These findings point to a complex cross-talk between VEGF and MMPs in the progression of ovarian tumor and suggest the possibility of using VEGF inhibitors to affect MMP-dependent tumor invasion.
Pubmed
Journal: PloS one
January/9/2013
Abstract
Podocyte or endothelial cell VEGF-A knockout causes thrombotic microangiopathy in adult mice. To study the mechanism involved in acute and local injury caused by low podocyte VEGF-A we developed an inducible, podocyte-specific VEGF-A knockdown mouse, and we generated an immortalized podocyte cell line (VEGF(KD)) that downregulates VEGF-A upon doxycycline exposure. Tet-O-siVEGF:podocin-rtTA mice express VEGF shRNA in podocytes in a doxycycline-regulated manner, decreasing VEGF-A mRNA and VEGF-A protein levels in isolated glomeruli to ~20% of non-induced controls and urine VEGF-A to ~30% of control values a week after doxycycline induction. Induced tet-O-siVEGF:podocin-rtTA mice developed acute renal failure and proteinuria, associated with mesangiolysis and microaneurisms. Glomerular ultrastructure revealed endothelial cell swelling, GBM lamination and podocyte effacement. VEGF knockdown decreased podocyte fibronectin and glomerular endothelial alpha(V)beta(3) integrin in vivo. VEGF receptor-2 (VEGFR2) interacts with beta(3) integrin and neuropilin-1 in the kidney in vivo and in VEGF(KD) podocytes. Podocyte VEGF knockdown disrupts alpha(V)beta(3) integrin activation in glomeruli, detected by WOW1-Fab. VEGF silencing in cultured VEGF(KD) podocytes downregulates fibronectin and disrupts alpha(V)beta(3) integrin activation cell-autonomously. Collectively, these studies indicate that podocyte VEGF-A regulates alpha(V)beta(3) integrin signaling in the glomerulus, and that podocyte VEGF knockdown disrupts alpha(V)beta(3) integrin activity via decreased VEGFR2 signaling, thereby damaging the three layers of the glomerular filtration barrier, causing proteinuria and acute renal failure.
Pubmed
Journal: European journal of applied physiology
September/4/2013
Abstract
We previously reported that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion (vibroX) markedly improves cycling endurance capacity, increases capillary-to-fibre ratio and skeletal muscle oxidative enzyme activity in untrained young women. These findings are intriguing, since increases in oxidative muscle phenotype and endurance capacity are typically induced by endurance but not heavy resistance exercise. Here, we tested the hypothesis that vibroX activates genes associated with mitochondrial biogenesis and angiogenesis. Eight healthy, recreationally resistance-trained young men performed either vibroX or resistance exercise (RES) in a randomised, cross-over design. Needle biopsies (M. vastus lateralis) were obtained at rest and 3 h post-exercise. Changes in relative gene expression levels were assessed by real-time quantitative PCR. After vibroX, vascular endothelial growth factor and peroxisome proliferator-activated receptor-γ coactivator 1α mRNA abundances increased to 2- and 4.4-fold, respectively, but did not significantly change above resting values after RES. Other genes involved in mitochondrial biogenesis were not affected by either exercise modality. While vibroX increased the expression of hexokinase II, xanthine dehydrogenase, and manganese superoxide dismutase mRNA, there were no changes in these transcripts after RES. This study demonstrates that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion activates metabolic and angiogenic gene programs, which are usually activated after endurance but not resistance exercise. Thus, targeted modification of high load resistance exercise by vibration and vascular occlusion might represent a novel strategy to induce endurance-type muscle adaptations.
Pubmed
Journal: International journal of cancer
November/29/2007
Abstract
Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc(+) cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70% and 80%, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32%, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50% by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically.
Pubmed
Journal: Oncology reports
November/27/2007
Abstract
Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the initial step in biosynthesis of prostaglandins (PGs) from arachidonic acid. COX-2 has been associated with inflammatory processes and tumorigenesis. In order to investigate the correlation between VEGF, COX-2 expression, and tumorigenesis in primary central nervous system lymphomas (PCNSLs), the present study assessed 26 cases of PCNSL by immunostaining for VEGF and COX-2. Immunohistochemical studies were evaluated as follows: (-), no staining; (1+), 0-30% positive cells; (2+), 30-60% positive cells; (3+), >60% positive cells. VEGF expression was detected in 21 of 26 cases; of these, 14, 1 and 6 were scored as 3+, 2+ and 1+, respectively. COX-2 expression was detected in 22 of 26 cases; of these, 14, 4 and 4 were scored as 3+, 2+ and 1+, respectively. For double immunofluorescence, 20 of 26 cases that were detected with both VEGF and COX-2 were examined and almost all tumor cells coexpressed both VEGF and COX-2 in the examined cases. However, COX-2 and VEGF expression in PCNSLs did not correlate with neoangiogenesis and patient survival in the present study, in contrast to previous findings in systemic lymphomas. It is suggested that the high frequency of COX-2 and VEGF coexpression in PCNSLs may be associated with tumorigenesis of PCNSLs and could possibly lead to a future therapeutic trial of PCNSLs with selective COX-2 inhibitor therapy.
Pubmed
Journal: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
January/26/2011
Abstract
Degenerative disorders of the intervertebral discs (IVDs) are generally characterized by enhanced matrix degradation, angiogenesis, innervation, and increased expression of catabolic cytokines. In this study, we investigated the effects of inflammatory cytokines, IL-1β, and TNF-α, on the expression of an angiogenic factor, vascular endothelial growth factor (VEGF), and neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in human IVD degeneration. IL-1β and TNF-α stimulated the gene expression of VEGF, NGF, and BDNF in nucleus pulposus (NP) cells isolated from patient tissues. Immunohistochemical results demonstrated a positive correlation between IL-1β and VEGF/NGF/BDNF expression in human IVD tissues. RNA expression analysis of patient tissues also identified positive correlations between VEGF and platelet endothelial cell adhesion molecule-1 (PECAM-1) and between NGF/BDNF and protein gene product 9.5 (PGP9.5). Our findings suggest that IL-1β is generated during IVD degeneration, which stimulates the expression of VEGF, NGF, and BDNF, resulting in angiogenesis and innervation.
Pubmed
Journal: Current neurovascular research
April/8/2009
Abstract
There is significant evidence to suggest that a dysfunctional blood-brain barrier [BBB] may contribute to the pathogenesis of some Alzheimer's disease [AD] lesions. An indicator for this could be diminished capillary vascular endothelial growth factor [VEGF] and / or endothelial nitric oxide synthase [eNOS] activity in AD brains. Cortical samples were taken from the superior temporal and calcarine cortices of ten confirmed AD and ten non-demented comparison brains. Contiguous coronal sections were stained using immunohistochemistry techniques to stain for tau protein, beta-amyloid [Abeta] n-termini ([40 & 42]), VEGF and eNOS. Standardized regions of cortex were randomly selected. Areas of ten contiguous field-diameters of comparable and full cortical widths were observed in each section and the densities of neurofibrillary tangles [NFTs], senile plaques [SPs] and Abeta, VEGF and eNOS positive capillaries were recorded. In both AD cortices there were significant inverse correlations found between both VEGF and eNOS-positive microvessels and the presence of NFTs, and each of the amyloid isoforms in SPs and amyloid-positive capillaries [p < 0.01]. In addition there was a significant positive correlation between VEGF and eNOS densities in both cortices [p< 0.01].These results suggest that diminished VEGF and eNOS activity in particularly lesion prone regions of AD brains may contribute to the pathogenesis of NFT and / or SP lesions.
Pubmed
Journal: Tissue engineering. Part A
September/26/2010
Abstract
BACKGROUND
While several studies report that bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) can act synergistically to improve bone tissue engineering, others suggest that VEGF inhibits osteogenesis. The purpose of these experiments was therefore to evaluate the effect of dual transfection of these growth factors and potential mechanisms of interaction on gene expression and osteogenesis in vitro and in vivo.
METHODS
Marrow-derived mesenchymal stem cells (MSCs) were exposed to recombinant VEGF protein or transfected with adenoviruses encoding BMP2, VEGF, or LacZ in a variety of ratios. Alterations in gene and protein expression in vitro as well as bone formation in vivo were assessed.
RESULTS
MSC exposure to AdV-VEGF or recombinant VEGF inhibited BMP2 mRNA expression, protein production, and MSC differentiation. Coculture experiments revealed that BMP2 suppression occurs through both an autocrine and a paracrine mechanism, occurring at the transcriptional level. Compared to controls, cotransfection of VEGF and BMP2 transgenes prevented ectopic bone formation in vivo.
CONCLUSIONS
VEGF is a potent inhibitor of BMP2 expression in MSCs, and supplementation or overexpression of VEGF inhibits osteogenesis in vitro and ectopic bone formation in vivo. Strategies to utilize MSCs in bone tissue engineering therefore require careful optimization and precise delivery of growth factors for maximal bone formation.
Pubmed
Journal: Biochemical and biophysical research communications
December/8/2002
Abstract
In skeletal muscles, angiogenesis can be induced by increases in wall shear stress. To identify molecules involved in the angiogenic process, a method based on the use of BS-1 lectin-coated magnetic beads was developed to isolate a cellular fraction enriched in microvascular endothelial cells which are directly exposed to wall shear stress. Using such cellular fractions from skeletal muscles of C57 mice in which angiogenesis was induced by administration with the alpha(1)-adrenergic antagonist prazosin, we found the concentration of vascular endothelial growth factor (VEGF) increased in correlation to the duration of the prazosin stimulus. In contrast, the angiopoietin-2/tie-2 system was not changed even after 4days of prazosin treatment. In neuronal nitric oxide synthase (nNOS) knockout mice, the VEGF concentration was also elevated after prazosin treatment but remained almost unchanged in endothelial nitric oxide synthase (eNOS) knockout mice. However, eNOS (and not nNOS) knockout mice expressed higher levels of VEGF under non-stimulated conditions as compared to C57 mice. These results suggest that VEGF produced in endothelial cells is involved in angiogenesis in skeletal muscles of mice responding to the administration of systemic vasodilators. NO derived from eNOS and nNOS may be an important regulator of the angiogenic response in skeletal muscles in vivo.
Pubmed
Journal: The Journal of international medical research
April/3/2016
Abstract
OBJECTIVE
Angiogenesis depends on interaction between a variety of promoting and inhibiting factors, and is known to involve vascular endothelial growth factor (VEGF) A and the Notch signaling pathway. The present study investigated the expression of Notch ligand delta-like (DLL) 4 (Drosophila), and VEGFA in colon cancer and colorectal adenoma tissue, and the association with tumour angiogenesis.
METHODS
Protein level DLL4, VEGFA and CD34 molecule (CD34) expression was detected immunohistochemically in tissue sections from patients with colon cancer and colorectal adenoma.
RESULTS
Out of 80 cases (35 with colon cancer, 45 with colorectal adenoma) DLL4 and VEGFA expression was closely related to tumour diameter, clinical stage, histological grade and lymph node metastasis. DLL4 expression was significantly higher in colon cancer tissue than colorectal adenoma tissue.
CONCLUSIONS
High levels of DLL4 expression were closely related to metastasis and prognosis in patients with colon cancer. The results of the present study support the conclusion that prognosis of colon cancer is significantly correlated with angiogenesis.
Pubmed
Journal: Microvascular research
October/1/2017
Abstract
Anti-angiogenesis has been proposed as an important strategy for angiogenesis-related diseases. Cryptotanshinone (CPT), an active component of Salvia miltiorrhiza, may be a potential inhibitor of angiogenesis. However, the molecular mechanisms underlying its anti-angiogenic activities remain poorly understood. This study is to investigate the effects of CPT on VEGF-induced angiogenesis and VEGFR2 signaling pathway in human umbilical vein endothelial cells (HUVECs).
HUVECs were treated with different concentration of CPT (5-20μmol/L) and the viability, endothelial cell migration, invasion, and tubular-like structure formation of HUVECs were detected by MTT, wound-healing migration, Transwell invasion and Matrigel tube formation assays, respectively. To assess the effect of CPT on VEGFR2 signaling pathway, VEGF-induced phosphorylation of VEGFR2 and its downstream molecules, including ERK1/2, p90RSK, Src and FAK were analyzed by Western blot.
CPT significantly suppressed VEGF-induced cells proliferation, migration, invasion, and tubular-like structure formation in HUVECs in a dose- and time-dependent manner. Western blot results revealed that CPT significantly suppressed VEGF-induced phosphorylation of VEGFR2 and its key downstream protein kinases, including p-ERK1/2, p-p90RSK, pY416-Src and pY576/577-FAK, which are responsible for endothelial cell migration, proliferation, and survival.
Our study suggested that CPT potently inhibits VEGF-induced angiogenesis by suppressing VEGFR2 activation and its downstream Src/FAK and ERK1/2 signaling pathways in HUVECs, highlighting the therapeutic potential for the treatment of angiogenesis-related diseases.
Pubmed
Journal: Nan fang yi ke da xue xue bao = Journal of Southern Medical University
May/22/2013
Abstract
OBJECTIVE
To characterize a new alternative splicing isoform of human vascular endothelial growth factor (VEGF) gene.
METHODS
The total RNA was extracted from the lung tissue of a legally aborted 4-month-old fetus and amplified by RT-PCR. The amplified product was cloned into the plasmid pMD18-T and plasmid pcDNA3.1- for sequence analysis.
RESULTS
Electrophoresis of the RT-PCR products displayed one short band for VEGF(121) (487 bp) and a long band. The latter was characterized to contain two fragments: one was normal VEGF(165) (619 bp), and the other (639 bp) had an identical nucleotide sequence to VEGF(165) with a 20 bp fragment inserted between exons 3 and 4. Sequence analysis showed that this 20-bp nucleotide was inserted from the 3' end of the third intron containing a splicing signal, thus causing shift mutation in the reading frame of VEGF gene and early appearance of the stop codon UAG in the middle of exon 4.
CONCLUSIONS
A new alternative splicing isoform of VEGF probably exists in the lung tissue of a legally aborted human fetus, and its biological significance remains to be further investigated.
Pubmed
Journal: Journal of clinical immunology
September/22/2008
Abstract
BACKGROUND
Kawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that mainly occurs in infants and children. Clinical and histopathologic findings suggest that vascular endothelial growth factor (VEGF) is involved in the coronary artery lesions (CALs) development in KD. This study hypothesized that specific VEGF gene polymorphisms and their haplotypes are associated with KD susceptibility and CAL development in Taiwanese children.
METHODS
The VEGF -2578 A/C, -634 G/C, and +936 C/T single-nucleotide polymorphisms (SNPs) were genotyped in 156 children with KD and 672 ethnically matched healthy controls using the Pre-Developed TaqMan Allelic Discrimination Assay.
RESULTS
No significant differences in genotype, allele, carrier, and haplotype frequencies of the three SNPs were found between healthy controls and children with KD or between patients with and without CAL.
CONCLUSIONS
Our data suggest that VEGF -2578 A/C, -634 G/C, and +936 C/T SNPs do not confer increased susceptibility to KD or to CAL development.
Pubmed
Journal: Journal of biological regulators and homeostatic agents
November/15/2015
Abstract
Breast cancer, a malignant tumor frequently occurring in females, is traditionally treated with excision. In the search for a new treatment, we analyzed the influence of CoCl2 on MCF-7 cell proliferation of breast cancer and tumor angiogenesis factor and discussed the results. Having applied CoCl2 as chemical hypoxia-induced agent, in-vitro MCF-7 cell hypoxia model of breast cancer was established, after which methyl thiazolyl tetrazolium (MTT) staining was performed in detecting inhibitory action of CoCl2 to proliferation of MCF-7 cells cultured in-vitro, and inverted phase contrast microscope was adopted to observe morphological changes of MCF-7 cell in hypoxia model. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) was made to determine how CoCl2 influences mRNA expression changes of hypoxia inducible factor-1α (HIF-1α), chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF) in MCF-7 cells. Western blot was designed to study and record data on the influence of CoCl2 on protein expression changes of HIF-1α, CXCR4 and VEGF. As a result, CoCl2 was proved to control MCF-7 cell proliferation and increase expression of HIF-1α, CXCR4 and VEGF.
Authors
Pubmed
Journal: American journal of human genetics
March/16/2013
Abstract
About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.
Pubmed
Journal: Neuron
January/8/2014
Abstract
Nerves and vessels often run parallel to one another, a phenomenon that reflects their functional interdependency. Previous studies have suggested that neurovascular congruency in planar tissues such as skin is established through a "one-patterns-the-other" model, in which either the nervous system or the vascular system precedes developmentally and then instructs the other system to form using its established architecture as a template. Here, we find that, in tissues with complex three-dimensional structures such as the mouse whisker system, neurovascular congruency does not follow the previous model but rather is established via a mechanism in which nerves and vessels are patterned independently. Given the diversity of neurovascular structures in different tissues, guidance signals emanating from a central organizer in the specific target tissue may act as an important mechanism to establish neurovascular congruency patterns that facilitate unique target tissue function.
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