Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as diabetic retinopathy and retinopathy of prematurity. Thus far, mediators of nitrative stress have been poorly characterized. We recently described that trans-arachidonic acids are major products of NO2•-mediated isomerization of arachidonic acid within the cell membrane, but their biological relevance is unknown. Here we show that trans-arachidonic acids are generated in a model of retinal microangiopathy in vivo in a NO•-dependent manner. They induce a selective time- and concentration-dependent apoptosis of microvascular endothelial cells in vitro, and result in retinal microvascular degeneration ex vivo and in vivo. These effects are mediated by an upregulation of the antiangiogenic factor thrombospondin-1, independently of classical arachidonic acid metabolism. Our findings provide new insight into the molecular mechanisms of nitrative stress in microvascular injury and suggest new therapeutic avenues in the management of disorders involving nitrative stress, such as ischemic retinopathies and encephalopathies.
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The authors wish to thank H. Fernandez for her technical skills and help. This work was supported by grants from the Canadian Institutes of Health Research, the March of Dimes Birth Defects Foundation, the Heart and Stroke Foundation of Québec, the Fonds de la Recherche en Santé du Québec, Le Réseau de Recherche en Santé de la Vision and La Fondation du NO. E.K.-D. is recipient of a fellowship award from the 'Association des Juniors en Pédiatrie/Gallia' (France). F.S. and S.C. are recipients of fellowship and scientist awards, respectively, from the Canadian Institutes of Health Research. S.B. and M.S. are recipients of studentships from the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada, respectively. P.H. is supported by grants from the Hospital For Sick Children Foundation and Fonds de la Recherche en Santé du Québec. M.B. is supported by grants from the US National Institutes of Health (R01 GM62453) and Philip Morris USA, Inc. S.C. also holds a Canada Research Chair (perinatology). The authors thank M. Febbraio and J. Lawler, who provided the CD36 and TSP-1 knockout animals, respectively.
The authors declare no competing financial interests.
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Kermorvant-Duchemin, E., Sennlaub, F., Sirinyan, M. et al. Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1–dependent microvascular degeneration. Nat Med 11, 1339–1345 (2005) doi:10.1038/nm1336
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