title: Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy.
abstract: Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A2 (TxA2), we tested whether TxA2 plays a role in retinal vasoobliteration of OIR and contributes to such vascular degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retinal vasoobliteration in rat pups (80% O2 exposure from postnatal days 5-14) was associated with increased TxB2 generation and was significantly prevented by TxA2 synthase inhibitor CGS-12970 (10 mg x kg(-1) x day(-1)) or TxA2-receptor antagonist CGS-22652 (10 mg x kg(-1) x day(-1)). TxA2 mimetics U-46619 (EC50 50 nM) and I-BOP (EC50 5 nM) caused a time- and concentration-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; other prostanoids did not cause cell death. The peroxidation product 8-iso-PGF2, which is generated in OIR, stimulated TxA2 formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA2-dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA2 in vasoobliteration of OIR and unveil a so far unknown function for TxA2 in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA2 might participate in other ischemic neurovascular injuries.
authors.affiliation: Department of Pediatrics, Research Center, Hôpital Sainte-Justine, Montreal, Quebec H3T 1C5, Canada.
authors.forename: M H
authors.initials: MH
authors.lastname: Beauchamp
authors.forename: A K
authors.initials: AK
authors.lastname: Martinez-Bermudez
authors.forename: F
authors.initials: F
authors.lastname: Gobeil
authors.forename: A M
authors.initials: AM
authors.lastname: Marrache
authors.forename: X
authors.initials: X
authors.lastname: Hou
authors.forename: G
authors.initials: G
authors.lastname: Speranza
authors.forename: D
authors.initials: D
authors.lastname: Abran
authors.forename: C
authors.initials: C
authors.lastname: Quiniou
authors.forename: P
authors.initials: P
authors.lastname: Lachapelle
authors.forename: J
authors.initials: J
authors.lastname: Roberts
authors.forename: G
authors.initials: G
authors.lastname: Almazan
authors.forename: D R
authors.initials: DR
authors.lastname: Varma
authors.forename: S
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012164:Retinal Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013928:Thromboxane A2 / Q000502:physiology*
chemical_list: D013778:Tetrazolium Salts; D013844:Thiazoles; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D010100:Oxygen