Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy.
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.
Beauchamp
M H
MH
Department of Pediatrics, Research Center, Hôpital Sainte-Justine, Montreal, Quebec H3T 1C5, Canada.
Martinez-Bermudez
A K
AK
Gobeil
F
F
Marrache
A M
AM
Hou
X
X
Speranza
G
G
Abran
D
D
Quiniou
C
C
Lachapelle
P
P
Roberts
J
J
Almazan
G
G
Varma
D R
DR
Chemtob
S
S
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*
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