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F. Sennlaub, E. Kermorvant, M. Balazy, M. Beauchamp, S. Brault, D. Checcin, C. Quiniou, S. Chemtob; Trans–arachidonic acids (TAAs) increase in oxygen induced retinopathy and induce retinal endothelial cell death via a thrombospondin–1–dependent pathwayv . Invest. Ophthalmol. Vis. Sci. 2004;45(13):741.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Nitro–oxidative stress is an important factor in the genesis of retinovascular injury as observed in ROP. But mediators of nitrosative stress remain for the most part unknown. Trans–arachidonic acids (TAAs) are recently described major products of NO2– radical–mediated isomerization of arachidonic acid. We investigated the effects and mode of action of TAAs on newborn retinal microvasculature. Methods: The role of nitrosative products in microvascular degeneration secondary to O2–induced retinopathy was determined by treatment of O2–exposed rat pups with NO2–/ONOO– scavenger FeTPPs. Retinal vascular density was studied after intravitreal injection of TAAs to newborn animals; similar experiments were conducted on retinal explants. In addition, viability of neuroretino–vascular cultured microvascular endothelial, astroglial and smooth muscle cells was determined by MTT (tetrazolium salt 3–(4,5–dimethyl thiazol–2yl)–2,5–diphenyl tetrazolium bromide) assay. Nature of cell death was assessed at different times by propidium iodide incorporation and Annexin V expression (using fluorescence–activated cell sorting). Results: O2–induced retinal vasoobliteration was prevented by the NO2–/ONOO– scavenger FeTPPs; retinal TAA levels rose in this model. Intravitreal injection of TAAs induced a retinal vasoobliteration; these effects were reproduced ex vivo on retinal explants. Clarification of cell type susceptibility was established on cultured neuroretino–vascular cells. TAAs induced a time– and concentration–dependent endothelial cell death; astrocytes, smooth muscle and non–neural endothelial cells were unaffected. The endothelial cell death was consistent with one of necrapoptotic nature. TAAs induced an upregulation of anti–proliferative thrombospondin–1 along with decreased expression of VEGF receptor–2. Moreover, anti–thrombospondin–1 neutralizing antibody completely prevented endothelial cell death. Conclusions: Data uncover new mediators of nitrosative stress in newborn retinal microvascular injury as seen in ROP, namely the TAAs, which in turn exert specific retinal endothelial cytotoxicity via a thrombospondin–1–dependent pathway.
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