© 2000 American Heart Association, Inc.
Vascular Biology |
Nitric Oxide Induces the Synthesis of Vascular Endothelial Growth Factor by Rat Vascular Smooth Muscle Cells
From the Department of Clinical Biochemistry (J.D., A.D-K., A.J., I.G., A.Z., D.Z-G., I.F., A.W.), Collegium Medicum, Jagiellonian University, Kraków, Poland; and the Falk Cardiovascular Research Center (A.S., J.P.C.), Stanford University, Stanford, Calif.
Correspondence to Dr Józef Dulak, Department of Cardiology, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail josef.dulak{at}uklibk.ac.at
Abstract—Vascular
endothelial growth factor (VEGF) is known to induce the
release of nitric oxide (NO) from endothelial cells.
However, the effect of NO on VEGF synthesis is not clear. Accordingly,
the effect of endogenous and exogenous NO on VEGF synthesis
by rat vascular smooth muscle cells (VSMCs) was investigated. Two in
vitro models were used: (1) VSMCs stimulated to produce NO by treatment
with interleukin (IL)-1ß (10 ng/mL) and (2) VSMCs lipotransfected
with pKecNOS plasmid, containing the endothelial
constitutive NO synthase (ecNOS) cDNA. The synthesis of NO was
inhibited by
N
-nitro-L-arginine methyl
ester (L-NAME, 2 to 5 mmol/L) or diaminohydroxypyrimidine (DAHP,
2.5 to 5 mmol/L), inhibitors of NOS and GTP
cyclohydrolase I, respectively. Some cells treated with L-NAME or DAHP
were supplemented with L-arginine (10 mmol/L) or
tetrahydrobiopterin (BH4; 100 µmol/L), respectively.
In addition, we studied the effect of sodium nitroprusside (SNP; 10 and
100 µmol/L) and chemically related compounds, potassium
ferrocyanide and ferricyanide, on VEGF generation. IL-1ß induced iNOS
expression and NO generation and significantly upregulated VEGF mRNA
expression and protein synthesis. L-NAME and DAHP totally inhibited NO
generation and decreased the IL-1ß–upregulated VEGF synthesis by
30% to 40%. Supplementation with L-arginine or
BH4 increased NO generation by L-NAME– or DAHP-treated
cells, and VEGF synthesis was augmented by addition of BH4.
The cells generating NO after pKecNOS transfection released
significantly higher amounts of VEGF than cells transfected with
control plasmids. Inhibition of NO generation by L-NAME decreased VEGF
synthesis. In contrast to the effect of endogenous NO, we
observed the inhibition of VEGF synthesis in the presence of high (10
or 100 µmol/L) concentrations of SNP. This effect was mimicked
by chemically related ferricyanide and ferrocyanide compounds,
suggesting that the inhibitory effect of sodium
nitroprusside may be mediated by an NO-independent mechanism. The
results indicate that endogenous NO enhances VEGF
synthesis. The positive interaction between endogenous NO
and VEGF may have implications for endothelial
regeneration after balloon angioplasty and for angiogenesis.
Key Words: VEGF • nitric oxide • atherosclerosis • tetrahydrobiopterin • gene transfer
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