Journal
FASEB JOURNAL
Volume 22, Issue 9, Pages 3207-3215Publisher
WILEY
DOI: 10.1096/fj.07-103804
Keywords
metalloproteinases; collagenase-3; inducible nitric oxide synthase; caveolin-1; wound healing
Categories
Funding
- Ministerio de Educacion y Ciencia
- Programa Ramon y Cajal
- Plan Nacional de I + D + I [SAF 2005-06025, SAF 2006-02410]
- European Union [FEDER 2FD97-1432]
- Spanish Society of Nephrology
- Ministerio de Sanidad y Consumo
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Nitric oxide (NO) plays a critical role in wound healing, in part by promoting angiogenesis. However, the precise repair pathways affected by NO are not well defined. We now show that NO regulates matrix metalloproteinase-13 (MMP-13) release during wound repair. We find that normally MMP-13 is kept inside endothelial cells by an association with caveolin-1. However, nitration of MMP-13 on tyrosine residue Y338 causes it to dissociate from caveolin-1 and be released from endothelial cells. We next explored the functional significance of MMP-13 nitration in vivo. Skin injury increases nitration of MMP-13 in mice. Skin wounds in inducible nitric oxide synthase knockout mice release less MMP-13 and heal more slowly than skin wounds in wild-type mice. Conversely, skin wounds in caveolin-1 knockout mice have increased NO production, increased MMP-13 nitration, and accelerated wound healing. Collectively, our data reveal a new pathway through which NO modulates wound repair: nitration of MMP-13 promotes its release from endothelial cells, where it accelerates angiogenesis and wound healing.
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