scholarly journals Retinoic Acid Pathway Regulation of Vascular Endothelial Growth Factor in Ovine Amnion

2018 ◽  
Vol 26 (10) ◽  
pp. 1351-1359 ◽  
Author(s):  
Cecilia Y. Cheung ◽  
Debra F. Anderson ◽  
Marion Rouzaire ◽  
Loïc Blanchon ◽  
Vincent Sapin ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Gene Promoters ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Pregnant Sheep ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) has been proposed as an important regulator of amniotic fluid absorption across the amnion into the fetal vasculature on the surface of the placenta. However, the activators of VEGF expression and action in the amnion have not been identified. Using the pregnant sheep model, we aimed to investigate the presence of the retinoic acid (RA) pathway in ovine amnion and to determine its effect on VEGF expression. Further, we explored relationships between RA receptors and VEGF and tested the hypothesis that RA modulates intramembranous absorption (IMA) through induction of amnion VEGF in sheep fetuses subjected to altered IMA rates. Our study showed that RA receptor isoforms were expressed in sheep amnion, and RA response elements (RAREs) were identified in ovine RARβ and VEGF gene promoters. In ovine amnion cells, RA treatment upregulated RARβ messenger RNA (mRNA) and increased VEGF transcript levels. In sheep fetuses, increases in IMA rate was associated with elevated VEGF mRNA levels in the amnion but not in the chorion. Further, RARβ mRNA was positively correlated with VEGF mRNA levels in the amnion and not chorion. We conclude that an RA pathway is present in ovine fetal membranes and that RA is capable of inducing VEGF. The finding of a positive relationship between amnion VEGF and RARβ during altered IMA rate suggests that the retinoid pathway may play a role through VEGF in regulating intramembranous transport across the amnion.

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.

scholarly journals Synergistic Up-Regulation of Vascular Endothelial Growth Factor (VEGF) Expression in Macrophages by Adenosine A2AReceptor Agonists and Endotoxin Involves Transcriptional Regulation via the Hypoxia Response Element in the VEGF Promoter

2007 ◽  
Vol 18 (1) ◽  
pp. 14-23 ◽  
Author(s):  
Madhuri Ramanathan ◽  
Grace Pinhal-Enfield ◽  
Irene Hao ◽  
Samuel Joseph Leibovich
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Transcriptional Regulation ◽  
Growth Factor ◽  
Promoter Activity ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Macrophages are an important source of vascular endothelial growth factor (VEGF). Adenosine A2Areceptor (A2AR) agonists with Toll-like receptor (TLR) 2, 4, 7, and 9 agonists synergistically induce macrophage VEGF expression. We show here using VEGF promoter-luciferase reporter constructs that the TLR4 agonist Escherichia coli lipopolysaccharide (LPS) and the A2AR agonists NECA and CGS21680 synergistically augment VEGF transcription in macrophages and that the HRE in the VEGF promoter is essential for this transcription. We examined whether LPS and/or NECA induce HIF-1α expression. HIF-1α mRNA levels were increased in LPS-treated macrophages in an NF-κB–dependent manner; NECA strongly increased these levels in an A2AR-dependent manner. LPS induced luciferase expression from a HIF-1α promoter-luciferase construct in an A2AR-independent manner. Further stimulation with NECA did not increase HIF-1α promoter activity, indicating that the A2AR-dependent increase in HIF-1α mRNA is post-transcriptional. LPS/NECA treatment also increased HIF-1α protein and DNA binding levels. Deletion of putative NF-κB–binding sites from the VEGF promoter did not affect LPS/NECA-induced VEGF promoter activity, suggesting that NF-κB is not directly involved in VEGF transcription. Taken together, these data indicate that LPS/NECA-induced VEGF expression involves transcriptional regulation of the VEGF promoter by HIF-1α through the HRE. HIF-1α is transcriptionally induced by LPS and post-transcriptionally up-regulated in an A2AR-dependent manner.

scholarly journals Expression of vascular endothelial growth factor in the growth plate is stimulated by estradiol and increases during pubertal development

2010 ◽  
Vol 205 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Joyce Emons ◽  
Andrei S Chagin ◽  
Torun Malmlöf ◽  
Magnus Lekman ◽  
Åsa Tivesten ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Plate ◽  
Bone Growth ◽  
Pubertal Development ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Epiphyseal Growth Plate ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Longitudinal bone growth is regulated in the growth plate. At the end of puberty, growth velocity diminishes and eventually ceases with the fusion of the growth plate through mechanisms that are not yet completely understood. Vascular endothelial growth factor (VEGF) has an important role in angiogenesis, but also in chondrocyte differentiation, chondrocyte survival, and the final stages of endochondral ossification. Estrogens have been shown to up-regulate VEGF expression in the uterus and bone of rats. In this study, we investigated the relation between estrogens and VEGF production in growth plate chondrocytes both in vivo and in vitro. The expression of VEGF protein was down-regulated upon ovariectomy and was restored upon estradiol (E2) supplementation in rat growth plates. In cultured rat chondrocyte cell line RCJ3.1C5.18, E2 dose dependently stimulated 121 and 189 kDa isoforms of VEGF, but not the 164 kDa isoform. Finally, VEGF expression was observed at both protein and mRNA levels in human growth plate specimens. The protein level increased during pubertal development, supporting a link between estrogens and local VEGF production in the growth plate. We conclude that estrogens regulate VEGF expression in the epiphyseal growth plate, although the precise role of VEGF in estrogen-mediated growth plate fusion remains to be clarified.

scholarly journals Hypoxic Regulation of Vascular Endothelial Growth Factor mRNA Stability Requires the Cooperation of Multiple RNA Elements

1999 ◽  
Vol 10 (4) ◽  
pp. 907-919 ◽  
Author(s):  
J. A. Dibbens ◽  
D. L. Miller ◽  
A. Damert ◽  
W. Risau ◽  
M. A. Vadas ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Coding Region ◽  
Vegf Gene ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Rapid Degradation ◽  
Multiple Regions ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a key regulator of developmental, physiological, and tumor angiogenesis. Upregulation of VEGF expression by hypoxia appears to be a critical step in the neovascularization of solid cancers. The VEGF mRNA is intrinsically labile, but in response to hypoxia the mRNA is stabilized. We have systematically analyzed the regions in the VEGF mRNA that are responsible for its lability under normoxic conditions and for stabilization in response to hypoxia. We find that the VEGF mRNA not only contains destabilizing elements in its 3′ untranslated region (3′UTR), but also contains destabilizing elements in the 5′UTR and coding region. Each region can independently promote mRNA degradation, and together they act additively to effect rapid degradation under normoxic conditions. Stabilization of the mRNA in response to hypoxia is completely dependent on the cooperation of elements in each of the 5′UTR, coding region, and 3′UTR. Combinations of any of two of these three regions were completely ineffective in responding to hypoxia, whereas combining all three regions allowed recapitulation of the hypoxic stabilization seen with the endogenous VEGF mRNA. We conclude that multiple regions in the VEGF mRNA cooperate both to ensure the rapid degradation of the mRNA under normoxic conditions and to allow stabilization of the mRNA in response to hypoxia. Our findings highlight the complexity of VEGF gene expression and also reveal a mechanism of gene regulation that could become the target for strategies of therapeutic intervention.

scholarly journals Antagonistic Functions of Tetradecanoyl Phorbol Acetate-Inducible-Sequence 11b and HuR in the Hormonal Regulation of Vascular Endothelial Growth Factor Messenger Ribonucleic Acid Stability by Adrenocorticotropin

2006 ◽  
Vol 20 (4) ◽  
pp. 916-930 ◽  
Author(s):  
Nadia Cherradi ◽  
Cyrille Lejczak ◽  
Agnes Desroches-Castan ◽  
Jean-Jacques Feige
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Nuclear Export ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Adrenocortical Cells ◽  
Tetradecanoyl Phorbol Acetate ◽  
Endothelial Growth Factor ◽  
Vegf Mrna Expression

Abstract Expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a potent angiogenic factor, is up-regulated by a variety of factors including hypoxia, growth factors, and hormones. In the adrenal cortex, regulation of VEGF expression by the pituitary hormone ACTH ensures the maintenance of the organ vasculature. We have previously shown that ACTH evokes a rapid and transient increase in VEGF mRNA levels in primary adrenocortical cells through transcription-independent mechanisms. We further demonstrated that the zinc finger RNA-binding protein Tis11b (tetradecanoyl phorbol acetate-inducible-sequence 11b) destabilizes VEGF mRNA through its 3′-untranslated region (3′-UTR) and that Tis11b is involved in the decay phase of ACTH-induced VEGF mRNA expression. In the present study, we attempted to determine the mechanisms underlying ACTH-elicited increase in VEGF mRNA levels in adrenocortical cells. We show that ACTH triggers an increase in the levels of the mRNA-stabilizing protein HuR in the cytoplasm and a concomitant decrease in the levels of HuR in the nucleus. This process is accompanied by an increased association of HuR with the nucleocytoplasmic shuttling protein pp32, indicating that ACTH induces HuR translocation from the nuclear to the cytoplasmic compartment. Leptomycin B, a specific inhibitor of CRM1-dependent nuclear export of pp32, significantly reduced ACTH-induced VEGF mRNA levels. Furthermore, RNA interference-mediated depletion of HuR in adrenocortical cells abrogated ACTH-induced VEGF mRNA expression. Finally, we show that Tis11b and HuR exert antagonistic effects on VEGF 3′-UTR in vitro. Although both proteins could bind simultaneously on VEGF 3′-UTR, Tis11b markedly decreases HuR-binding to this RNA sequence. Altogether, these results suggest that the RNA-stabilizing protein HuR is instrumental to ACTH-induced expression of VEGF mRNA and that the nuclear export of HuR is a rate-limiting step in this process. HuR appears to transiently stabilize VEGF transcripts after ACTH stimulation of adrenocortical cells, and Tis11b appears to subsequently trigger their degradation.

scholarly journals Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells

1997 ◽  
Vol 273 (5) ◽  
pp. H2224-H2231 ◽  
Author(s):  
Rama Natarajan ◽  
Wei Bai ◽  
Linda Lanting ◽  
Noe Gonzales ◽  
Jerry Nadler
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Endothelial ◽  
Ang Ii ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Mrna And Protein Expression ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF), in addition to its growth-promoting effects on endothelial cells, can also increase vascular permeability and monocyte migration. It has therefore been implicated in the pathogenic neovascularization associated with diabetic retinopathy and atherosclerosis. However, the factors regulating VEGF expression in the vascular wall are not fully understood. In this study, we examined the regulation of VEGF expression in vascular smooth muscle cells (VSMC) by hyperglycemia as well as by angiotensin II (ANG II). We also examined whether the 12-lipoxygenase (12-LO) product 12-hydroxyeicosatetraenoic acid (12-HETE) can alter VEGF expression, since 12-LO products of arachidonic acid have angiogenic properties, and ANG II as well as high glucose (HG, 25 mM) can increase 12-LO activity and expression in VSMC. Studies were carried out in human (HSMC) or porcine VSMC (PSMC), which were cultured for at least two passages under normal glucose (NG, 5.5 mM) or HG conditions. HG culture alone increased the expression of VEGF mRNA and protein in both HSMC and PSMC. Furthermore, ANG II treatment significantly induced VEGF mRNA and protein expression only in VSMC cultured in HG and not NG. In addition, 12-HETE significantly increased VEGF mRNA and protein expression in HSMC cultured in NG as well as in HG. Cells cultured in HG also secreted significantly greater amounts of VEGF into the culture medium. These results suggest that elevated VEGF production under HG conditions may play a role in the accelerated vascular disease observed in diabetes.

Pregnancy augments uteroplacental vascular endothelial growth factor gene expression and vasodilator effects

1997 ◽  
Vol 273 (2) ◽  
pp. H938-H944 ◽  
Author(s):  
Y. Ni ◽  
V. May ◽  
K. Braas ◽  
G. Osol
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Kinase Inhibitor ◽  
Northern Blotting ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Uterine Arteries ◽  
Growth Factor Gene ◽  
Endothelial Growth Factor

This study examined a potential role for vascular endothelial growth factor (VEGF) in uterine artery remodeling and vasodilation during pregnancy. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect VEGF mRNA in uterine tissues from nonpregnant (NP), midpregnant (MP, 15-16 days), and late-pregnant (LP, 19-21 days) rats and in placentas from MP and LP rats. VEGF mRNA levels in uteri and placentas were determined by Northern blotting, and the vasorelaxant activity of recombinant human VEGF (rh-VEGF) was tested and compared in isolated uterine arteries from LP and NP animals. VEGF120 and VEGF164 were the major isoforms detected in uterine tissues; all members of the VEGF family (VEGF120, VEGF164, VEGF188, and VEGF205) were expressed in LP placentas. VEGF mRNA levels increased 60% in MP and 80% in LP above those in NP (P < 0.05) in uterine tissues; VEGF mRNA levels were also detectable in placentas and elevated approximately fivefold in LP vs. MP tissues (P < 0.01). Phenylephrine-preconstricted uterine arcuate arteries (NP and LP) dilated in response to rhVEGF, an effect that was completely abolished by endothelial denudation or pretreatment with genistein, a tyrosine kinase inhibitor. The magnitude of dilation to an intermediate concentration of rhVEGF (1 nM) was greater in LP than in NP vessels (55 +/- 8 vs. 24 +/- 11%; P < 0.05), and this effect was diminished comparably in both groups (approximately 60% by N omega-nitro-L-arginine, an inhibitor of nitric oxide synthesis. These results suggest that VEGF may play a role in the vascular remodeling and vasodilation that lead to decreased uterine vascular resistance and increased uterine blood flow during pregnancy.

Expression of Vascular Endothelial Growth Factor in Human Monocyte/Macrophages Stimulated with Lipopolysaccharide

2001 ◽  
Vol 85 (01) ◽  
pp. 171-176 ◽  
Author(s):  
Hiroyuki Itaya ◽  
Hidemi Yoshida ◽  
Masayuki Koyama ◽  
Sohei Suzuki ◽  
Kei Satoh ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Map Kinase ◽  
Human Monocyte ◽  
P38 Map Kinase ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Endothelial Growth Factor

SummaryVascular endothelial growth factor (VEGF) is a mitogen for endothelial cells. We have studied the production of VEGF by human macrophages in response to lipopolysaccharide (LPS). Macrophages stimulated with LPS expressed VEGF mRNA and protein in concentration- and time-dependent manners. The LPS-induced expression of VEGF was inhibited by cycloheximide pretreatment, which suggested that synthesis of certain factor(s) is required for the LPS activity. The induction of VEGF was also suppressed by SB203580, an inhibitor of p38 mitogen-activated protein (MAP) kinase. These results suggest that the LPS-induced VEGF expression depends on the p38-mediated expression of c-Jun, which constitutes the AP-1 complex and binds to the AP-1 site in the VEGF promoter. Pretreatment of the cells with dexamethasone did not affect the LPS-induced upregulation of VEGF mRNA but strongly inhibited VEGF protein production, and the involvement of posttranscriptional regulation on VEGF expression by dexamethasone was suggested. The conditioned medium of LPS-stimulated macrophages enhanced the growth of cultured endothelial cells and it was inhibited by an antibody against VEGF. We conclude that macrophages produce VEGF in response to the stimulation with LPS, which may be partly mediated by the p38 MAP kinase pathway.

scholarly journals Tristetraprolin Inhibits Ras-dependent Tumor Vascularization by Inducing Vascular Endothelial Growth Factor mRNA Degradation

2007 ◽  
Vol 18 (11) ◽  
pp. 4648-4658 ◽  
Author(s):  
Khadija Essafi-Benkhadir ◽  
Cercina Onesto ◽  
Emmanuelle Stebe ◽  
Christoph Moroni ◽  
Gilles Pagès
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Antitumor Agent ◽  
Mrna Degradation ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Angiogenic Potential ◽  
Angiogenic Switch ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is one of the most important regulators of physiological and pathological angiogenesis. Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and overexpression of VEGF are common denominators of tumors from different origins. We have established a new link between these two fundamental observations converging on VEGF mRNA stability. In this complex phenomenon, tristetraprolin (TTP), an adenylate and uridylate-rich element-associated protein that binds to VEGF mRNA 3′-untranslated region, plays a key role by inducing VEGF mRNA degradation, thus maintaining basal VEGF mRNA amounts in normal cells. ERKs activation results in the accumulation of TTP mRNA. However, ERKs reduce the VEGF mRNA-destabilizing effect of TTP, leading to an increase in VEGF expression that favors the angiogenic switch. Moreover, TTP decreases RasVal12-dependent VEGF expression and development of vascularized tumors in nude mice. As a consequence, TTP might represent a novel antiangiogenic and antitumor agent acting through its destabilizing activity on VEGF mRNA. Determination of TTP and ERKs status would provide useful information for the evaluation of the angiogenic potential in human tumors.

scholarly journals Statins Augment Vascular Endothelial Growth Factor Expression in Osteoblastic Cells via Inhibition of Protein Prenylation

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 681-692 ◽  
Author(s):  
Toyonobu Maeda ◽  
Tetsuya Kawane ◽  
Noboru Horiuchi
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Mrna Expression ◽  
Osteoblastic Cells ◽  
Vascular Endothelial ◽  
Protein Prenylation ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Endothelial Growth Factor ◽  
Vegf Mrna Expression

Statins such as simvastatin are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that inhibit cholesterol synthesis. We presently investigated statin effects on vascular endothelial growth factor (VEGF) expression in osteoblastic cells. Hydrophobic statins including simvastatin, atorvastatin, and cerivastatin–but not a hydrophilic statin, pravastatin–markedly increased VEGF mRNA abundance in nontransformed osteoblastic cells (MC3T3-E1). Simvastatin (10−6m) time-dependently augmented VEGF mRNA expression in MC3T3-E1 cells, mouse stromal cells (ST2), and rat osteosarcoma cells (UMR-106). According to heterogeneous nuclear RNA and Northern analyses, 10−6m simvastatin stimulated gene expression for VEGF in MC3T3-E1 cells without altering mRNA stability. Transcriptional activation of a VEGF promoter-luciferase construct (−1128 to +827), significantly increased by simvastatin administration. As demonstrated by gel mobility shift assay, simvastatin markedly enhanced the binding of hypoxia-responsive element-protein complexes. These results indicate that the stimulation of the VEGF gene by simvastatin in MC3T3-E1 cells is transcriptional in nature. VEGF secretion into medium was increased in MC3T3-E1 by 10−6m simvastatin. Pretreating MC3T3-E1 cells with mevalonate or geranylgeranyl pyrophosphate, a mevalonate metabolite, abolished simvastatin-induced VEGF mRNA expression; manumycin A, a protein prenylation inhibitor, mimicked statin effects on VEGF expression. The effect of simvastatin was blocked by pretreatment with wortmannin and LY294002, specific phosphatidylinositide-3 kinase inhibitors. Simvastatin enhanced mineralized nodule formation in culture, whereas coincubation with mevalonate, geranylgeranyl pyrophosphate, LY294002, or VEGF receptor 2 inhibitor (SU1498) abrogated statin-induced mineralization. Thus, statins stimulate VEGF expression in osteoblasts via reduced protein prenylation and the phosphatidylinositide-3 kinase pathway, promoting osteoblastic differentiation.

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