While it is well established that tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) induces apoptosis in various cell types, the role of TRAIL in regulation of retinal neovascularization (NV) has not been described. Here we determined the role of TRAIL in retinal NV during oxygen-induced retinopathy using TRAIL deficient ( ؊/؊ ) mice. TRAIL and its receptor, DR5, were expressed in wild-type retinas at all time points evaluated (postnatal days 12, 17, 21, 24) during oxygen-induced retinopathy and in agematched room air control animals. Localization of TRAIL ؉ cells within the neovascular tufts of hyperoxiaexposed wild-type mice suggested TRAIL plays a role in oxygen-induced retinopathy. Retinal vascular development appeared normal in the TRAIL ؊/؊ mice, except for a small but significant difference in the capillary-free zone surrounding major arteries. A minimal difference in avascularity was observed at postnatal day 12 in the retinas of TRAIL ؊/؊ mice after hyperoxia-exposure compared with wild-type mice , suggesting that TRAIL does not play a major role in the vaso-obliterative phase of oxygen-induced retinopathy. However, at the peak of NV, TRAIL ؊/؊ mice had a significant increase in retinal neovascularization. In addition, when NV naturally regresses in wild-type mice, TRAIL ؊/؊ mice continued to display significantly high levels of NV. This was attributed to a significant decrease in neovascular tuft cells undergoing apoptosis in TRAIL ؊/؊ mice. Together, these data strongly suggest that TRAIL plays a role in the control of retinal NV.
EphrinB2 ligands and EphB4 receptors are expressed on endothelial cells (EC) of arteries and veins respectively, and are essential for vascular development. To understand how these molecules regulate retinal neovascularization (NV), we evaluated their expression in a model of oxygen-induced retinopathy (OIR). EphrinB2 and EphB4 were expressed on arterial and venous trunks respectively, and on a subset of deep capillary vessels. EphB4 expression was reduced following hyperoxia, while ephrinB2 expression remained unaltered. In addition, a subset of EphB4 positive veins regressed in a caspase-3 dependent manner during hyperoxia. Arteriovenous malformations were also observed with loss of arterial-venous boundaries. Finally, both ephrinB2 and EphB4 were expressed on a subset of neovascular tufts following hyperoxia. These data confirm the contribution of ECs from both venous and arterial origins to the development retinal NV.
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