Vascular caveolin deficiency supports the angiogenic effects of nitrite, a major end product of nitric oxide metabolism in tumors
| Autor: | Chantal Dessy, Irina Lobysheva, Bernard Gallez, Olivier Feron, Françoise Frérart |
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| Přispěvatelé: | UCL - MD/MINT - Département de médecine interne, UCL - MD/FARM - Ecole de pharmacie, UCL - (SLuc) Service de médecine nucléaire |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Nitric Oxide Synthase Type III Angiogenesis Caveolin 1 Nitric Oxide Synthase Type II Down-Regulation Mice Transgenic Nitric Oxide Nitric oxide chemistry.chemical_compound Mice Enos Caveolin Animals Nitrite RNA Small Interfering Molecular Biology Nitrites Aorta chemistry.chemical_classification Analysis of Variance biology Neovascularization Pathologic Metabolism Neoplasms Experimental Nitrite reductase biology.organism_classification Cell Hypoxia Disease Models Animal Enzyme Oncology chemistry Cancer research Female Neoplasm Transplantation |
| Zdroj: | Molecular Cancer Research, Vol. 7, no. 7, p. 1056-1063 (2009) |
| Popis: | The biological status of nitrite recently evolved from an inactive end product of nitric oxide (NO) metabolism to a major intravascular and tissue storage of NO. Several enzymes and proteins may indeed work as nitrite reductases. The endothelial NO synthase (eNOS) is proposed to be one of them, particularly when oxygen is lacking. Here, we examined whether the lack of caveolin, a scaffold protein known to limit eNOS activity under basal conditions and to be down-regulated in tumor vessels, could favor the reconversion of nitrite into NO and thereby promote angiogenesis. We found that nitrite-rich serum from caveolin-deficient mice and exogenous nitrite exert proangiogenic effects on aortic explants cultured in a three-dimensional collagen matrix. We identified a higher intrinsic capacity of caveolin-deficient vessels and endothelial cells to convert nitrite into bioactive NO. These effects did occur under moderate hypoxia and were abolished on exposure to a NO scavenger. Evidence for eNOS acting as a nitrite reductase derived from the failure to reproduce the proangiogenic effects of nitrite on eNOS-deficient aorta rings and endothelial cells. Finally, in a mouse tumor model, we documented the higher nitrite content in hypoxic tumors and identified inducible NO synthase as the major source of nitrite. Altogether, these data identify the lack of caveolin observed in the tumor vasculature as a favorable ground for nitrite-driven formation of endothelial tubes in the hypoxic tumor microenvironment. This work also strengthens the therapeutic value of the modulation of caveolin expression to interfere with tumor angiogenesis. (Mol Cancer Res 2009;7(7):1056–63) |
| Databáze: | OpenAIRE |
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