scholarly journals Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis.

2003 ◽  
Vol 50 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Hideo Kimura ◽  
Hiroyasu Esumi
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Heme Oxygenase 1 ◽  
No Production ◽  
Vascular Endothelial ◽  
Vegf Gene ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Physiologically, angiogenesis is tightly regulated, or otherwise it leads to pathological processes, such as tumors, inflammatory diseases, gynecological diseases and diabetic retinopathy. The vascular endothelial growth factor (VEGF) is a potent and critical inducer of angiogenesis. The VEGF gene expression is regulated by a variety of stimuli. Hypoxia is one of the most potent inducers of the VEGF expression. The hypoxia inducible factor 1 (HIF-1) plays as a key transcription factor in hypoxia-mediated VEGF gene upregulation. Nitric oxide (NO) as well as hypoxia is reported to upregulate the VEGF gene by enhancing HIF-1 activity. The Akt/protein kinase B (PKB) pathway may be involved in NO-mediated HIF-1 activation in limited cell lines. There are some reports of negative effects of NO on HIF-1 and VEGF activity. These conflicting data of NO effects may be attributed mainly to the amount of released NO. Indeed, NO can be a positive or negative modulator of the VEGF gene under the same conditions simply by changing its amounts. The VEGF-mediated angiogenesis requires NO production from activated endothelial NO synthase (eNOS). Activation of eNOS by VEGF involves several pathways including Akt/PKB, Ca(2+)/calmodulin, and protein kinase C. The NO-mediated VEGF expression can be regulated by HIF-1 and heme oxygenase 1 (HO-1) activity, and the VEGF-mediated NO production by eNOS can be also modulated by HIF-1 and HO-1 activity, depending upon the amount of produced NO. These reciprocal relations between NO and VEGF may contribute to regulated angiogenesis in normal tissues.

scholarly journals Relaxin Induces Rapid Dilation of Rodent Small Renal and Human Subcutaneous Arteries via PI3 Kinase and Nitric Oxide

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2786-2796 ◽  
Author(s):  
Jonathan T. McGuane ◽  
Julianna E. Debrah ◽  
Laura Sautina ◽  
Yagna P. R. Jarajapu ◽  
Jacqueline Novak ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Peptide Hormone ◽  
Mesenteric Arteries ◽  
No Production ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

The peptide hormone relaxin is a potent vasodilator with therapeutic potential in diseases complicated by vasoconstriction, including heart failure. However, the molecular mediators and magnitude of vasodilation may vary according to duration of exposure and artery type. The objective of these studies was to determine mechanisms of rapid (within minutes) relaxin-induced vasodilation and to examine whether relaxin dilates arteries from different animal species and vascular beds. Rat and mouse small renal, rat mesenteric, and human sc arteries were isolated, mounted in a pressure arteriograph, and treated with recombinant human relaxin (rhRLX; 1–100 ng/ml) after preconstriction with phenylephrine. Rat and mouse small renal as well as human sc arteries dilated in response to rhRLX, whereas rat mesenteric arteries did not. Endothelial removal or pretreatment with l-NG-monomethyl arginine (L-NMMA) abolished rapid relaxin-induced vasodilation; phosphatidylinositol-3-kinase (PI3K) inhibitors also prevented it. In cultured human endothelial cells, rhRLX stimulated nitric oxide (assessed using 4-amino-5-methylamino-2′7′-difluorofluorescein) as well as Akt and endothelial NO synthase (eNOS) phosphorylation by Western blotting but not increases in intracellular calcium (evaluated by fura-2). NO production was attenuated by inhibition of Gαi/o and Akt (using pertussis toxin and the allosteric inhibitor MK-2206, respectively), PI3K, and NOS. Finally, the dilatory effect of rhRLX in rat small renal arteries was unexpectedly potentiated, rather than inhibited, by pretreatment with the vascular endothelial growth factor receptor inhibitor SU5416. We conclude that relaxin rapidly dilates select arteries across a range of species. The mechanism appears to involve endothelial Gαi/o protein coupling to PI3K, Akt, and eNOS but not vascular endothelial growth factor receptor transactivation or increased calcium.

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 Enhanced Vascular Endothelial Growth Factor Gene Expression in Ischaemic Skin of Critical Limb Ischaemia Patients

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Silvia Bleda ◽  
Joaquín de Haro ◽  
Francisco Acin ◽  
César Varela ◽  
Leticia Esparza
Keyword(s):  
Gene Expression ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Critical Limb Ischaemia ◽  
Control Group ◽  
Venous Disease ◽  
Vascular Endothelial ◽  
Vegf Gene ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Objectives. To perform a quantitative analysis of the vascular endothelial growth factor (VEGF) gene transcription in the skin of ischemic legs and provide information for VEGF in the pathogenesis in critical limb ischemia (CLI).Methods. Skin biopsies were obtained from 40 patients with CLI. Control samples came from 44 patients with chronic venous disease. VEGF gene expression was analysed using quantitative polymerase chain reaction.Results. Patients with CLI had higher skin VEGF expression than control group (RQ: 1.3 ± 0.1 versus 1,P=0.04).Conclusions. We found an association between ischemic skin and an elevated VEGF expression in legs from patients with CLI. These data support that the mechanism for VEGF upregulation in hypoxia conditions is intact and acts appropriately in the ischaemic limbs from patients with CLI.

scholarly journals Differential regulation of vascular endothelial growth factor and its receptor fms-like-tyrosine kinase is mediated by nitric oxide in rat renal mesangial cells

1999 ◽  
Vol 338 (2) ◽  
pp. 367-374 ◽  
Author(s):  
Stefan FRANK ◽  
Birgit STALLMEYER ◽  
Heiko KÄMPFER ◽  
Christian SCHAFFNER ◽  
Josef PFEILSCHIFTER
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Mesangial Cells ◽  
Differential Regulation ◽  
Moderate Increase ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Under conditions associated with local and systemic inflammation, mesangial cells and invading immune cells are likely to be responsible for the release of large amounts of nitric oxide (NO) in the glomerulus. To further define the mechanisms of NO action in the glomerulus, we attempted to identify genes which are regulated by NO in rat glomerular mesangial cells. We identified vascular endothelial growth factor (VEGF) and its receptor fms-like tyrosine kinase (FLT-1) to be under the regulatory control of exogenously applied NO in these cells. Using S-nitroso-glutathione (GSNO) as an NO-donating agent, VEGF expression was strongly induced, whereas expression of its FLT-1 receptor simultaneously decreased. Expressional regulation of VEGF and FLT-1 mRNA was transient and occurred rapidly within 1–3 h after GSNO treatment. Expression of a second VEGF-specific receptor, fetal liver kinase-1 (FLK-1/KDR), could not be detected. The inflammatory cytokine interleukin-1β mediated a moderate increase in VEGF expression after 24 h and had no influence on FLT-1 expression. In contrast, platelet-derived growth factor–BB and basic fibroblast growth factor had no effect on VEGF expression, but strongly induced FLT-1 mRNA levels. Obviously, there is a differential regulation of VEGF and its receptor FLT-1 by NO, cytokines and growth factors in rat mesangial cells.

Regulation of Vascular Endothelial Growth Factor Gene Expression in Murine Macrophages by Nitric Oxide and Hypoxia

2003 ◽  
Vol 228 (6) ◽  
pp. 697-705 ◽  
Author(s):  
Madhuri Ramanathan ◽  
Avi Giladi ◽  
S. Joseph Leibovich
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cell Density ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Ifn Γ ◽  
Cell Densities ◽  
Endothelial Growth Factor ◽  
Vegf Protein

Vascular endothelial growth factor (VEGF) expression in murine peritoneal macrophages is strongly upregulated by hypoxia via transcriptional and posttranscriptional mechanisms. Interferon-γ (IFN-γ) with Escherichia coll lipopolysaccharide (LPS) also upregulates expression of VEGF, as well as of the inducible nitric oxide synthase (INOS). Hypoxia (1% O2) upregulates VEGF expression in macrophages from both wild-type and INOS knockout mice, indicating that hypoxic upregulation of VEGF is independent of INOS. However, the INOS inhibitor aminoguanidine (AG) decreases the VEGF expression induced by LPS/IFN-γ, indicating an important role for NO. NO-dependent induction of VEGF is strongly dependent on cell density. LPS/IFN-γ treatment induces minimal VEGF protein expression in macrophages cultured at low cell densities (<0.25 × 106 cells/cm2); at higher cell densities (>0.25 × 106 cells/cm2) that lead to conditions of pericellular hypoxia, however, induction of VEGF expression was strong. Transient transfection of RAW 264.7 cells with luciferase reporter constructs of the murine VEGF promoter indicates that both hypoxia and LPS/IFN-γ independently induce VEGF promoter activity, irrespective of cell density. Although LPS/IFN-γ treatment induces transcriptional activation of the VEGF promoter, significant levels of VEGF protein are only expressed by cells at high density under conditions of pericellular hypoxia. This suggests an important regulatory role for hypoxia at the posttranscriptional level. Deletion analysis of the VEGF promoter shows that the hypoxia response element region and its immediate flanking sequences are essential for both hypoxia and LPS/IFN-γ-induced VEGF promoter activation.

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