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 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 (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-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.