Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy

• Published in: Journal of applied physiology (1985) 2001-06, Vol.90 (6), p.2279-2288
• Main Authors: Beauchamp, Martin H, Martinez-Bermudez, Ana Katherine, Gobeil, Fernand, Jr, Marrache, Anne Marilise, Hou, Xin, Speranza, Giovanna, Abran, Daniel, Quiniou, Christiane, Lachapelle, Pierre, Roberts, Jackson, II, Almazan, Guillermina, Varma, Daya R, Chemtob, Sylvain
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Animals; Animals, Newborn; Biological and medical sciences; Blood vessels; Capillaries - pathology; Capillaries - physiopathology; Cell Survival - drug effects; Cells; Cells, Cultured; DNA Fragmentation - drug effects; L-Lactate Dehydrogenase - metabolism; Medical sciences; Ophthalmology; Oxidation; Oxygen - toxicity; Rats; Rats, Sprague-Dawley; Retina; Retinal Diseases - metabolism; Retinal Diseases - pathology; Retinal Diseases - physiopathology; Retinal Vessels - drug effects; Retinal Vessels - physiology; Retinopathies; Tetrazolium Salts; Thiazoles; Thromboxane A2 - physiology
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/jappl.2001.90.6.2279

1  Departments of Pediatrics, Ophthalmology and Pharmacology, Research Center, Hôpital Sainte-Justine, Montreal, Quebec H3T 1C5; Departments of 2  Pharmacology and Therapeutics and 3  Ophthalmology, McGill University, Montreal, Quebec, Canada H3G 1Y6; and 4  Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, Tennessee 37232-6602 Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A 2 (TxA 2 ), we tested whether TxA 2 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% O 2 exposure from postnatal days 5-14 ) was associated with increased TxB 2 generation and was significantly prevented by TxA 2 synthase inhibitor CGS-12970 (10 mg · kg 1 · day 1 ) or TxA 2 -receptor antagonist CGS-22652 (10 mg · kg 1 · day 1 ). TxA 2 mimetics U-46619 (EC 50 50 nM) and I-BOP (EC 50 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-PGF 2 , which is generated in OIR, stimulated TxA 2 formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA 2 -dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA 2 in vasoobliteration of OIR and unveil a so far unknown function for TxA 2 in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA 2 might participate in other ischemic neurovascular injuries. endothelium; retina; necrosis; apoptosis; peroxidation