Nitric oxide elicits functional MMP‐13 protein‐tyrosine nitration during wound repair

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 caveo‐lin‐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.—Lizarbe, T. R., García‐Ram, C., Tarín, C., Saura, M., Calvo, E., López, J. A., López‐Otín, C., Folgueras, A. R., Lamas, S., Zaragoza, C. Nitric oxide elicits functional MMP‐13 protein‐tyrosine nitration during wound repair. FASEB J. 22, 3207–3215 (2008)