Mechanisms of vascular endothelial growth factor (VEGF) mediated nitric oxide (NO) signaling in transformed human endothelial cells – Say NO to survival!

Abstract Heme oxygenase (HO)-1 has been shown to be an important biological target of nitric oxide (NO). NO can induce HO-1 expression and IL-8 production, particularly, in endothelial cells. Interestingly, HO-1 tends to induce the production of vascular endothelial growth factor (VEGF) that is involved in endothelial IL-8 syntheses. Whether HO-1 expression by NO may provide a link with IL-8 or VEGF synthesis was investigated in human umbilical vein endothelial cells (HUVECs). The NO donor S-nitroso-N-acetyl-penicillamine (SNAP) dose-dependently increased IL-8 and VEGF productions and HO-1 expression in HUVECs. Transfection with either HO-1 small interfering RNA or HO-1 antisense oligodeoxynucleotide abrogated the ability of SNAP to induce HO-1 expression and IL-8 and VEGF productions. Both pharmacological induction and gene transfer of HO-1 directly induced IL-8 and VEGF productions. Anti-VEGF neutralizing antibody blocked SNAP-mediated IL-8 production and VEGF itself induced IL-8 production, whereas anti-IL-8 neutralizing antibody had no effect on VEGF production in SNAP-treated HUVECs. Neither anti-VEGF nor anti-IL-8 antibodies influenced SNAP-induced HO-1 expression. Moreover, neither VEGF nor IL-8 showed an additive effect on SNAP-induced HO-1 expression. HO-1 transfection had no significant effect on productions of other CXC chemokines, such as growth-related oncogen-α and epithelial neutrophil activation peptide-78. Taken together, these results provide a molecular cascade showing NO-HO-1-VEGF-IL-8 sequence in human endothelial cells.

Download Full-text

Faculty Opinions recommendation of MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717957529.793461935 ◽

2012 ◽

Author(s):

Paul Evans ◽

Jovana Serbanovic-Canic

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Growth Factor Signaling ◽

Vascular Endothelial ◽

Human Endothelial Cells ◽

Endothelial Growth Factor

Download Full-text

Pro-Angiogenic Effects of Resveratrol in Brain Endothelial Cells: Nitric Oxide-Mediated Regulation of Vascular Endothelial Growth Factor and Metalloproteinases

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.2 ◽

2012 ◽

Vol 32 (5) ◽

pp. 884-895 ◽

Cited By ~ 43

Author(s):

Fabricio Simão ◽

Aline S Pagnussat ◽

Ji Hae Seo ◽

Deepti Navaratna ◽

Wendy Leung ◽

...

Keyword(s):

Nitric Oxide ◽

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Signaling Pathways ◽

Tube Formation ◽

Mitogen Activated Protein Kinase ◽

Vascular Endothelial ◽

Cerebral Endothelial Cells ◽

Endothelial Growth Factor

Resveratrol may be a powerful way of protecting the brain against a wide variety of stress and injury. Recently, it has been proposed that resveratrol not only reduces brain injury but also promotes recovery after stroke. But the underlying mechanisms are unclear. Here, we tested the hypothesis that resveratrol promotes angiogenesis in cerebral endothelial cells and dissected the signaling pathways involved. Treatment of cerebral endothelial cells with resveratrol promoted proliferation, migration, and tube formation in Matrigel assays. Consistent with these pro-angiogenic responses, resveratrol altered endothelial morphology resulting in cytoskeletal rearrangements of β-catenin and VE-cadherin. These effects of resveratrol were accompanied by activation of phosphoinositide 3 kinase (PI3-K)/Akt and Mitogen-Activated Protein Kinase (MAPK)/ERK signaling pathways that led to endothelial nitric oxide synthase upregulation and increased nitric oxide (NO) levels. Subsequently, elevated NO signaling increased vascular endothelial growth factor and matrix metalloproteinase levels. Sequential blockade of these signaling steps prevented resveratrol-induced angiogenesis in cerebral endothelial cells. These findings provide a mechanistic basis for the potential use of resveratrol as a candidate therapy to promote angiogenesis and neurovascular recovery after stroke.

Download Full-text