Osteoblast expression of vascular endothelial growth factor is modulated by the extracellular microenvironment

2001 ◽  
Vol 280 (1) ◽  
pp. C72-C80 ◽  
Author(s):  
Jason A. Spector ◽  
Babak J. Mehrara ◽  
Joshua A. Greenwald ◽  
Pierre B. Saadeh ◽  
Douglas S. Steinbrech ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Lactate Concentration ◽  
Vascular Endothelial ◽  
Acidic Ph ◽  
Vegf Mrna ◽  
Hypoxic Conditions ◽  
Extracellular Microenvironment ◽  
Endothelial Growth Factor ◽  
Elevated Lactate

Angiogenesis, the formation of new blood vessels, is crucial to the process of fracture healing. Vascular disruption after osseous injury results in an acidic, hypoxic wound environment. We have previously shown that osteoblasts can produce vascular endothelial growth factor (VEGF) in response to a variety of stimuli. In this study we examined pH and lactate concentration, two components of the putative fracture extracellular microenvironment, and determined their relative contribution to regulation of rat calvarial osteoblast VEGF production under both normoxic and hypoxic conditions. Our results demonstrate that pH and lactate concentration do independently affect osteoblast VEGF mRNA and protein production. Acidic pH (7.0) significantly decreased VEGF production, under normoxic and hypoxic conditions ( P < 0.05), compared with neutral pH (7.4). This decrease was primarily transcriptionally regulated, because the rate of VEGF mRNA degradation was unchanged at pH 7.0 vs. 7.4. Similarly, an elevated lactate concentration (22 mM) also depressed osteoblast elaboration of VEGF at both neutral and acidic pH ( P < 0.001). Furthermore, the effects of increasing acidity and elevated lactate appeared to be additive.

scholarly journals The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF.

1993 ◽  
Vol 4 (12) ◽  
pp. 1317-1326 ◽  
Author(s):  
J E Park ◽  
G A Keller ◽  
N Ferrara
Keyword(s):  
Extracellular Matrix ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Angiogenic Potential ◽  
Molecular Masses ◽  
Matrix Bound ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms

Vascular endothelial growth factor (VEGF)mRNA undergoes alternative splicing events that generate four different homodimeric isoforms, VEGF121, VEGF165, VEGF189, or VEGF206. VEGF121 is a nonheparin-binding acidic protein, which is freely diffusible. The longer forms, VEGF189 or VEGF206, are highly basic proteins tightly bound to extracellular heparin-containing proteoglycans. VEGF165 has intermediate properties. To determine the localization of VEGF isoforms, transfected human embryonic kidney CEN4 cells expressing VEGF165, VEGF189, or VEGF206 were stained by immunofluorescence with a specific monoclonal antibody. The staining was found in patches and streaks suggestive of extracellular matrix (ECM). VEGF165 was observed largely in Golgi apparatus-like structures. Immunogold labeling of cells expressing VEGF189 or VEGF206 revealed that the staining was localized to the subepithelial ECM. VEGF associated with the ECM was bioactive, because endothelial cells cultured on ECM derived from cells expressing VEGF189 or VEGF206 were markedly stimulated to proliferate. In addition, ECM-bound VEGF can be released into a soluble and bioactive form by heparin or plasmin. ECM-bound VEGF189 and VEGF206 have molecular masses consistent with the intact polypeptides. The ECM may represent an important source of VEGF and angiogenic potential.

scholarly journals Pitfalls in the Measurement of Circulating Vascular Endothelial Growth Factor

2001 ◽  
Vol 47 (4) ◽  
pp. 617-623 ◽  
Author(s):  
Wolfgang Jelkmann
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Neutralizing Antibodies ◽  
Inflammatory Diseases ◽  
Vascular Endothelial ◽  
Malignant Diseases ◽  
Vegf Mrna ◽  
Medline Search ◽  
Healthy Humans ◽  
Endothelial Growth Factor

Abstract Background: Vascular endothelial growth factor (VEGF) is a protein with antiapoptotic, mitogenic, and permeability-increasing activities specific for vascular endothelium. VEGF mRNA, which has five isoforms, is produced by nonmalignant cells in response to hypoxia and inflammation and by tumor cells in constitutively high concentrations. Because VEGF plays a crucial role in physiological and pathophysiological angiogenesis, measurements of circulating VEGF are of diagnostic and prognostic value, e.g., in cardiovascular failures, inflammatory diseases, and malignancies. However, there are major quantitative differences in the published results. This review attempts to identify reasons for these disparities. Approach: The literature was reviewed through a Medline search covering 1995 to 2000. A selection of exemplary references had to be made for this perspective overview. Content: Data are included from studies on healthy humans, gynecological patients, and persons suffering from inflammatory or malignant diseases. The results indicate that competitive immunoassays detect the total amount of circulating VEGF, which enables observations regarding the increase in VEGF in pregnancy and preeclampsia to be made. In these cases, capture immunoassays utilizing neutralizing antibodies are insufficient because of an accompanying increase in VEGF-binding soluble receptors (sFlt-1). Measurements of circulating free VEGF are useful for study of malignant diseases, which are associated with both genetically and hypoxia-induced overproduction of VEGF. The VEGF isoform specificity of the antibodies is also critical because both VEGF121 and VEGF165 are secreted. It is important to consider that platelets and leukocytes release VEGF during blood clotting. Conclusions: Future efforts should concentrate on the balance between free VEGF, total VEGF, and sFlt-1. Plasma, rather than serum, should be used for analysis.

scholarly journals All-Trans Retinoic Acid Inhibits Vascular Endothelial Growth Factor Expression in a Cell Model of Neutrophil Activation

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1264-1270 ◽  
Author(s):  
Meng Kian Tee ◽  
Jean-Louis Vigne ◽  
Robert N. Taylor
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Vegf Gene ◽  
Vegf Mrna ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Neutrophil Differentiation ◽  
Endothelial Growth Factor

Infiltrating neutrophil granulocytes are a particularly rich source of vascular endothelial growth factor (VEGF) in the endometrium and may contribute to the angiogenesis of endometriosis lesions. The objective of this study is to evaluate the expression and regulation of VEGF in endometrial neutrophils and in a model of neutrophil differentiation relevant to endometriosis. Immunohistochemistry was performed on endometriosis patient biopsies and cultured neutrophil-like HL-60 cells were assessed. The study was set in a reproductive biology division within an academic medical center. Endometrial biopsies were performed on women with endometriosis and HL-60 cells were treated with all-trans retinoic acid (atRA) and dimethyl sulfoxide in vitro. Immunofluorescence histochemistry, VEGF mRNA and protein quantification, and transfection studies of VEGF gene promoter-luciferase constructs were all main outcome measures. Immunofluorescence studies verified the presence of neutrophils in eutopic endometrium from women with endometriosis. Examination of the regulation of VEGF using differentiated HL-60 cells as a model, revealed that atRA induced a dose- and time-dependent suppression of VEGF mRNA and protein. Transient transfection, truncation, EMSA, and site-directed mutagenesis of human VEGF promoter-luciferase constructs in HL-60 cells indicated that atRA repressed VEGF gene transcription via a direct repeat 1 element located between −443 and −431 bp relative to the transcription initiation site. Because retinoic acid is synthesized de novo in endometrial cells under the influence of progesterone, our findings suggest that the up-regulated VEGF and angiogenesis in tissue from women with endometriosis may reflect failure of neutrophil differentiation in these cases, and provide a rationale for retinoid therapy in this condition.

Cyclosporine Toxicity and Vascular Endothelial Growth Factor (VEGF).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3924-3924
Author(s):  
Peter Kubisz ◽  
Barbara Grandtnerova ◽  
Ludovit Laca ◽  
Jan Stasko
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Graft Function ◽  
Renal Tissue ◽  
Gingival Hyperplasia ◽  
Kidney Graft ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Healthy Control ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) is a potent angiogenic and endothelial cell-specific mitogen. Expression of VEGF mRNA is increased under hypoxia/ischemia conditions. Its role in the setting of clinical kidney transplantation (Tx) is currently under investigation. Majority of works are dealing with gene polymorphisms and/or renal tissue expression. The aim of the study was to evaluate serum VEGF concentrations after kidney Tx and its relationship to graft outcome. Thirty-five adult patients (17 male, 18 female) treated with cyclosporine A or tacrolimus, at least 1 month after Tx and 22 healthy control (17 male, 5 female). Patients with acute rejection or infection were excluded. Serum VEGF (S-VEGF) concentrations were measured by Quantikine Immunoassay, RD Systems. S-VEGF concentrations were significantly higher after Tx than in healthy control (556 ± 463 pg/ml, vs 145 ± 74 pg/ml, p< 0.0001). No correlation was found with age, gender, time after Tx or type of calcineurin inhibitor. However, a significant correlation was found between basaline S-VEGF and S-creatinine (p< 0.05), S-VEGF and S-creatinine six months after Tx (p< 0.01) and between S-VEGF and cyclosporine toxicity defined as a gingival hyperplasia or biopsy proven nephrotoxicity (202 ± 121 pg/ml in stable patients vs 741 ± 436 pg/ml in cyclosporine toxicity group, p< 0.001). During six months of follow up, the kidney graft function was stable in 100% of patients with S-VEGF concentration ≤ 145 pg/ml but only in 50% of patients with S-VEGF concentration > 145 pg/ml (p < 0,05). We conclude that the S-VEGF concentration seems to be a marker of cyclosporine toxicity and prospective graft function deterioration. S-VEGF could be helpful to select patients who would have benefit from an early switch of immunosuppression.

scholarly journals Vascular Endothelial Growth Factor Increases during Blood-Brain Barrier-Enhanced Permeability Caused byPhoneutria nigriventerSpider Venom

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Monique C. P. Mendonça ◽  
Edilene S. Soares ◽  
Leila M. Stávale ◽  
Evanguedes Kalapothakis ◽  
Maria Alice Cruz-Höfling
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Ion Channels ◽  
Growth Factor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Blood Brain ◽  
Calbindin D28k ◽  
Endothelial Growth Factor

Phoneutria nigriventerspider accidental envenomation provokes neurotoxic manifestations, which when critical, results in epileptic-like episodes. In rats,P. nigriventervenom (PNV) causes blood-brain barrier breakdown (BBBb). The PNV-induced excitotoxicity results from disturbances on Na+, K+and Ca2+channels and glutamate handling. The vascular endothelial growth factor (VEGF), beyond its angiogenic effect, also, interferes on synaptic physiology by affecting the same ion channels and protects neurons from excitotoxicity. However, it is unknown whether VEGF expression is altered following PNV envenomation. We found that adult and neonates rats injected with PNV showed immediate neurotoxic manifestations which paralleled with endothelial occludin,β-catenin, and laminin downregulation indicative of BBBb. In neonate rats, VEGF, VEGF mRNA, and Flt-1 receptors, glutamate decarboxylase, and calbindin-D28k increased in Purkinje neurons, while, in adult rats, the BBBb paralleled with VEGF mRNA, Flk-1, and calbindin-D28k increases and Flt-1 decreases. Statistically, the variable age had a role in such differences, which might be due to age-related unequal maturation of blood-brain barrier (BBB) and thus differential cross-signaling among components of the glial neurovascular unit. The concurrent increases in the VEGF/Flt-1/Flk-1 system in the cerebellar neuron cells and the BBBb following PNV exposure might imply a cytokine modulation of neuronal excitability consequent to homeostatic perturbations induced by ion channels-acting PNV neuropeptides. Whether such modulation represents neuroprotection needs further investigation.

Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart

1994 ◽  
Vol 267 (5) ◽  
pp. H1948-H1954 ◽  
Author(s):  
E. Hashimoto ◽  
T. Ogita ◽  
T. Nakaoka ◽  
R. Matsuoka ◽  
A. Takao ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Myocardial Cells ◽  
Vegf Mrna ◽  
Vascular Permeability Factor ◽  
Endothelial Growth Factor ◽  
Perfused Hearts ◽  
Cultured Myocardial Cells

Vascular endothelial growth factor (VEGF or vascular permeability factor), a direct-acting, endothelial cell-specific mitogen, has been suggested to be involved in development and maintenance of vasculatures in tumor neovascularization and in normal tissues. To investigate possible roles of VEGF in ischemic hearts, we studied induction of VEGF mRNA by ischemia and hypoxia using coronary artery-ligated hearts in vivo and perfused hearts and cultured myocardial cells in vitro. VEGF mRNA was potently induced by ischemia in the heart in vivo. In perfused hearts, maximum expression was rapidly induced (within 30 min) by transient reversible ischemia (5–10 min of ischemia) and lasted at least 3 h. Induction was also caused by hypoxia, which was confirmed in perfused hearts and cultured myocardial cells. These results suggest that induction of VEGF mRNA is upregulated by oxygen deprivation in the heart and that not only infarction but also chronic ischemia in the clinical setting could induce VEGF as a potent angiogenesis factor to stimulate coronary collateral formation.

scholarly journals Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes.

1995 ◽  
Vol 15 (10) ◽  
pp. 5363-5368 ◽  
Author(s):  
I Stein ◽  
M Neeman ◽  
D Shweiki ◽  
A Itin ◽  
E Keshet
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Half Life ◽  
Angiogenic Factor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Glut 1 ◽  
Induced Genes ◽  
Endothelial Growth Factor

Expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a potent angiogenic factor, is upregulated in response to a hypoxic or hypoglycemic stress. Here we show that the increase in steady-state levels of VEGF mRNA is partly due to transcriptional activation but mostly due to increase in mRNA stability. Both oxygen and glucose deficiencies result in extension of the VEGF mRNA half-life in a protein synthesis-dependent manner. Viewing VEGF as a stress-induced gene, we compared its mode of regulation with that of other stress-induced genes. Results showed that under nonstressed conditions, VEGF shares with the glucose transporter GLUT-1 a relatively short half-life (0.64 and 0.52 h, respectively), which is extended fourfold and more than eightfold, respectively, when cells are deprived of either oxygen or glucose. In contrast, the mRNAs of another hypoxia-inducible and hypoglycemia-inducible gene, grp78, as well as that of HSP70, were not stabilized by these metabolic insults. To show that VEGF and GLUT-1 are coinduced in differentially stressed microenvironments, multicell spheroids representing a clonal population of glioma cells in which each cell layer is differentially stressed were analyzed by in situ hybridization. Cellular microenvironments conducive to induction of VEGF and GLUT-1 were completely coincidental. These findings show that two different consequences of tissue ischemia, namely, hypoxia and glucose deprivation, induce VEGF and GLUT-1 expression by similar mechanisms. These proteins function, in turn, to satisfy the tissue needs through expanding its vasculature and improving its glucose utilization, respectively.

scholarly journals Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors.

1992 ◽  
Vol 3 (2) ◽  
pp. 211-220 ◽  
Author(s):  
B Berse ◽  
L F Brown ◽  
L Van de Water ◽  
H F Dvorak ◽  
D R Senger
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Permeability ◽  
Microvascular Permeability ◽  
Northern Analysis ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Vascular Permeability Factor ◽  
Permeability Factor ◽  
Endothelial Growth Factor

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), increases microvascular permeability and is a specific mitogen for endothelial cells. Expression of VPF/VEGF previously was demonstrated in a variety of tumor cells, in cultures of pituitary-derived cells, and in corpus luteum. Here we present evidence, by Northern analysis and in situ hybridization, that the VPF/VEGF gene is expressed in many adult organs, including lung, kidney, adrenal gland, heart, liver, and stomach mucosa, as well as in elicited peritoneal macrophages. The highest levels of VPF/VEGF transcripts were found in epithelial cells of lung alveoli, renal glomeruli and adrenal cortex, and in cardiac myocytes. The prominence of VPF/VEGF mRNA in these tissues suggests a possible role for VPF/VEGF in regulating baseline microvascular permeability, which is essential for tissue nutrition and waste removal. We also demonstrate particularly high VPF/VEGF mRNA levels in several human tumors, where it may be involved in promoting tumor angiogenesis and stroma generation, both as an endothelial cell mitogen and indirectly by its permeability enhancing effect that leads to the deposition of a provisional fibrin gel matrix.

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