© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF
aDepartment of Vascular Surgery, University of Vienna, AKH, Waehringer Guertel 18–20, A-1090 Vienna, Austria
bDepartment of Clinical Biochemistry, Collegium Medicum, Jagiellonian University, Krakow, Poland
cSection of Vascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
dDivision of Cardiology, Innsbruck University, Innsbruck, Austria
eDepartment of Cell Biochemistry, Institute of Molecular Biology, Jagiellonian University, Krakow, Poland
* Corresponding author. Tel.: +43-140-400-6798; fax: +43-140-400-6782 alicia.jozkowicz{at}akh-wien.ac.at
Objective: Vascular endothelial growth factor (VEGF) induces the release of nitric oxide (NO) from endothelial cells. There is also limited data suggesting that NO may enhance VEGF generation. Methods: To further investigate this interaction, we examined the effect of exogenous and endogenous NO on the synthesis of VEGF by rat and human vascular smooth muscle cells (VSMC) by exposing cells to exogenous NO donors, or to genetic augmentation of eNOS or iNOS. Results: NO-donors potentiated by 2-fold the generation of VEGF protein by rat or human VSMC. Similarly, rat or human VSMC transiently transfected with plasmid DNA encoding eNOS or iNOS, synthesized up to 3-fold more VEGF than those transfected with control plasmid DNA, an effect which was reversed after treatment with the NOS antagonist L-NAME. Rat VSMC stably transfected with pKeNOS plasmid, constitutively produced NO and released high concentrations of VEGF. In these cells, L-NAME significantly reduced NO synthesis and decreased VEGF generation. The VEGF protein produced by NOS-transfected VSMC was biologically active, as conditioned media harvested from these cells increased endothelial cell proliferation. Conclusion: These studies reveal that NO derived from NO-donors or generated by NOS within the cells, upregulates the synthesis of VEGF in vascular smooth muscle cells. Administration of NO donors, or augmentation of endogenous NO synthesis, may be an alternative approach in therapeutic angiogenesis.
KEYWORDS Endothelial factors; Gene expression; Growth factors; Nitric oxide; Signal transduction
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