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.
Kermorvant-Duchemin
Elsa
E
Department of Pediatrics, Ophthalmology and Pharmacology, Research Center, Hôpital Ste-Justine, 3175 Côte de Ste-Catherine, Montréal, Québec, H3T1C5, Canada.
Sennlaub
Florian
F
Sirinyan
Mirna
M
Brault
Sonia
S
Andelfinger
Gregor
G
Kooli
Amna
A
Germain
Stéphane
S
Ong
Huy
H
d'Orleans-Juste
Pedro
P
Gobeil
Fernand
F
Zhu
Tang
T
Boisvert
Chantal
C
Hardy
Pierre
P
Jain
Kavita
K
Falck
J Russel
JR
Balazy
Michael
M
Chemtob
Sylvain
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001095:Arachidonic Acids / Q000378:metabolism / Q000633:toxicity*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers; D003925:Diabetic Angiopathies / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000166:cytology* / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034421:Sus scrofa; D013778:Tetrazolium Salts; D013844:Thiazoles; D019700:Thrombospondin 1 / Q000378:metabolism*
D001095:Arachidonic Acids; D017931:DNA Primers; D013778:Tetrazolium Salts; D013844:Thiazoles; D019700:Thrombospondin 1; D009569:Nitric Oxide; C022616:thiazolyl blue