Nitric Oxide Synthesis Leads to Vascular Endothelial Growth Factor Synthesis via the NO/Cyclic Guanosine 3′,5′-Monophosphate (cGMP) Pathway in Human Corpus Cavernosal Smooth Muscle Cells

2008 ◽  
Vol 5 (7) ◽  
pp. 1623-1635 ◽  
Author(s):  
Kazuhiko Komori ◽  
Akira Tsujimura ◽  
Tetsuya Takao ◽  
Yasuhiro Matsuoka ◽  
Yasushi Miyagawa ◽  
...  
1999 ◽  
Vol 46 (3) ◽  
pp. 703-715 ◽  
Author(s):  
A Józkowicz ◽  
J Pankiewicz ◽  
J Dulak ◽  
L Partyka ◽  
I Wybrańska ◽  
...  

The regulation of vascular wall homeostasis by nitric oxide (NO) generated by endothelium is being intensively studied. In the present paper, the involvement of NO in the vascular endothelial growth factor (VEGF), insulin or leptin-stimulated proliferation of human endothelial cells (HUVEC) was measured by [3H]thymidine or bromodeoxyuridine incorporation. VEGF and insulin, but not leptin, increased NO generation in HUVEC, as detected with ISO-NO electrode. Proliferation of HUVEC induced by leptin was not changed or was higher in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME) a nitric oxide synthase (NOS) inhibitor. In contrast, L-NAME blunted the proproliferative effect of VEGF and insulin. Furthermore, we demonstrated that, in human arterial smooth muscle cells (hASMC) transfected with endothelial NOS (eNOS) gene, the generation of biologically active VEGF protein was NO-dependent. Inhibition of NO generation by L-NAME decreased the synthesis of VEGF protein and attenuated HUVEC proliferation induced by conditioned media from transfected hASMC. Endothelium-derived NO seems to participate in VEGF and insulin, but not leptin, mitogenic activity. Additionally, the small amounts of NO released from endothelial cells, as mimicked by eNOS transfection into hASMC, may activate generation of VEGF in sub-endothelial smooth muscle cells, leading to increased synthesis of VEGF protein necessary for turnover and restitution of endothelial cells.


2003 ◽  
Vol 50 (1) ◽  
pp. 69-79 ◽  
Author(s):  
Alicja Józkowicz ◽  
Józef Dulak

Heme oxygenase-1 (HO-1), an inducible enzyme degrading heme to biliverdin, iron and carbon monoxide, is involved in regulation of inflammation and angiogenesis. Tin protoporphyrin (SnPPIX) and zinc protoporphyrin (ZnPPIX) are commonly used as competitive inhibitors of HO-1. We aimed to compare the effects of SnPPIX and ZnPPIX on the production of vascular endothelial growth factor (VEGF), activity of inducible nitric oxide synthase (iNOS) and cell viability. All experiments were performed on rat vascular smooth muscle cells and murine RAW264.7 macrophages treated with 3-10 microM protoporphyrins. Some cells were additionally stimulated with IL-1beta or with lipopolysaccharide. After a 24 h incubation period SnPPIX and ZnPPIX significantly reduced the generation of VEGF in vascular smooth muscle cells and RAW264.7, both in resting and stimulated cells. The inhibitory potentials of both protoporphyrins on VEGF synthesis were very similar. In contrast, analysis of iNOS activity revealed that results obtained with different HO-1 inhibitors are discrepant. Generation of nitric oxide by iNOS was significantly increased by SnPPIX but strongly decreased by ZnPPIX. Similar differences were observed when cell viability was compared. SnPPIX improved the cell survival rate, whereas the same doses of ZnPPIX exerted some cytotoxic effects. In summary, SnPPIX and ZnPPIX can be used as HO-1 inhibitors in some experimental models. However, these compounds produce also HO-independent effects, which can make the interpretation of experiments very uncertain. Thus the involvement of the HO-1 pathway should be always confirmed by more specific methods.


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