Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration.
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 NO(2)(*)-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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- Thrombospondin 1
- Thiazoles
- Tetrazolium Salts
- Sus scrofa
- Reverse Transcriptase Polymerase Chain Reaction
- Retinal Vessels
- Rats, Sprague-Dawley
- Rats
- Nitric Oxide
- Neovascularization, Physiologic
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Thrombospondin 1
- Thiazoles
- Tetrazolium Salts
- Sus scrofa
- Reverse Transcriptase Polymerase Chain Reaction
- Retinal Vessels
- Rats, Sprague-Dawley
- Rats
- Nitric Oxide
- Neovascularization, Physiologic