Redox-dependent effects of nitric oxide on microvascular integrity in oxygen-induced retinopathy.
Opposing effects have been ascribed to nitric oxide (NO) on retinal microvascular survival. We investigated whether changes in the redox state may contribute to explain apparent conflicting actions of NO in a model of oxygen-induced retinal vasoobliteration. Retinal microvascular obliteration was induced by exposing 7-day-old rat pups (P7) for 2 or 5 days to 80% O(2). The redox state of the retina was assessed by measuring reduced glutathione and oxidative and nitrosative products malondialdehyde and nitrotyrosine. The role of NO on vasoobliteration was evaluated by treating animals with nitric oxide synthase (NOS) inhibitors (N-nitro-l-arginine; L-NA) and by determining NOS isoform expression and activity; the contribution of nitrosative stress was also determined in animals treated with the degradation catalyst of peroxynitrite FeTPPS or with the superoxide dismutase mimetic CuDIPS. eNOS, but not nNOS or iNOS, expression and activity were increased throughout the exposure to hyperoxia. These changes were associated with an early (2 days hyperoxia) decrease in reduced glutathione and increases in malondialdehyde and nitrotyrosine. CuDIPS, FeTPPS, and L-NA treatments for these 2 days of hyperoxia nearly abolished the vasoobliteration. In contrast, during 5 days exposure to hyperoxia when the redox state rebalanced, L-NA treatment aggravated the vasoobliteration. Interestingly, VEGFR-2 expression was respectively increased by NOS inhibition after short-term (2 days) exposure to hyperoxia and decreased during the longer hyperoxia exposure. Data disclose that the dual effects of NO on newborn retinal microvascular integrity in response to hyperoxia in vivo depend on the redox state and seem mediated at least in part by VEGFR-2.
Beauchamp
Martin H
MH
Department of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Ste-Justine, Montréal, Québec H3T 1C5, Canada.
Sennlaub
Florian
F
Speranza
Giovanna
G
Gobeil
Fernand
F
Checchin
Daniella
D
Kermorvant-Duchemin
Elsa
E
Abran
Daniel
D
Hardy
Pierre
P
Lachapelle
Pierre
P
Varma
Daya R
DR
Chemtob
Sylvain
S
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D007527:Isoenzymes / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D008315:Malondialdehyde / Q000032:analysis; D008665:Metalloporphyrins / Q000494:pharmacology; D008833:Microcirculation / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D012164:Retinal Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology*; D012459:Salicylates / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D000975:Antioxidants; D007527:Isoenzymes; D008665:Metalloporphyrins; D012459:Salicylates; C030865:copper bis(3,5-diisopropylsalicylate); D019335:Nitroarginine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase; D040301:Vascular Endothelial Growth Factor Receptor-2; D005978:Glutathione; D010100:Oxygen