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

Microvascular degeneration is an important event in oxygen-induced retinopa thy (OIR), a model of retinopathy of prematurity. Because oxidant stress ab undantly generates thromboxane A(2) (TxA(2)), we tested whether TxA(2) play s a role in retinal vasoobliteration of OIR and contributes to such vascula r degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retina l vasoobliteration in rat pups (80% O-2 exposure from postnatal days 5-14) was associated with increased TxB(2) generation and was significantly preve nted 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) mimetic s U-46619 (EC50 50 nM) and I-BOP (EC50 5 nM) caused a time- and concentrati on-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; othe r prostanoids did not cause cell death. The peroxidation product 8-iso-PGF( 2), which is generated in OIR, stimulated TxA(2) formation by endothelial c ells and triggered cell death; these effects were markedly diminished by CG S-12970. TxA(2)-dependent neuroretinovascular endothelial cell death was mo stly 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 un known function for TxA(2) in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA(2) might participate in other ischemic neurovascular injuries.