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K. E. Hubert, M. H. Davies, A. J. Stempel, T. S. Griffith, M. R. Powers; Delayed Regression of Retinal Neovascularization in TRAIL Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3295.
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Using a mouse model of oxygen-induced retinopathy (OIR), we characterize the role of TNF-Related Apoptosis-Inducing Ligand (TRAIL), in retinal neovascularization (NV) and regression.
C57BL/6 (B6) and TRAIL deficient (-/-) mice were exposed to 75% oxygen (O2) from postnatal day 7 (P7) to P12 and recovered in room air (RA). Eyes from O2 exposed and RA mice were obtained for histopathologic studies and RT-PCR analysis. PCR was used to examine retinal expression of TRAIL and its receptors in B6 mice. Immunostaining was performed for TRAIL and F4/80, a macrophage/microglia marker, in B6 retinas. Retinal vaso-obliteration and NV was assessed in lectin labeled retinal whole mounts from TRAIL-/- and B6 mice. NV was quantified in H&E stained sections. TUNEL assay was used to quantify vascular tuft cells undergoing apoptosis.
PCR analysis shows TRAIL and three of its receptors, TRAIL-R2 (DR5), TRAIL-R3, and osteoprotegerin, are expressed at all time points evaluated (P12, P14, P17, P21, P24) in both O2 exposed and RA control B6 retinas. Immunolabeling for TRAIL demonstrates expression of TRAIL+ cells within the NV tufts in both tissue sections and whole mounts of O2 exposed B6 mice. A subset of the TRAIL+ cells are also F4/80+. There is no difference in the central avascular area of TRAIL-/- compared to B6 mice in lectin stained retinal whole mounts at P12O2. At P17O2, TRAIL-/- mice (n=10) had 34.76 ± 2.61 (mean ± SEM) neovascular nuclei per section and B6 mice (n=10) had 25.05 ± 1.22 nuclei per section (p<0.004). In addition, at P21O2, TRAIL-/- mice (n=9) continued to have significantly more neovascular nuclei with 38.60 ± 7.49 as compared to B6 mice (n=10) with 9.83 ± 2.51 nuclei per section (p<0.002). At P17O2, in TRAIL-/- mice, 2.04 ± 0.21% of neovascular nuclei were apoptotic, while in B6 mice, 9.85 ± 1.09% were apoptotic (p<0.0001). At P21O2, in TRAIL-/- mice, 1.09 ± 1.43% of neovascular nuclei were apoptotic compared to 15.03 ± 4.26% in B6 mice (p<0.005).
In summary, TRAIL and its receptors are expressed in the RA and O2 exposed retina. TRAIL co-localizes with a subset of F4/80+ cells after oxygen exposure. TRAIL does not appear to play a role in the vaso-obliterative phase of OIR. However, compared to B6 mice, TRAIL-/- mice show increased NV at P17O2, the peak of NV, as well as at P21O2 when regression of NV is expected to have occurred. Furthermore, there is a decrease in the percentage of neovascular tuft apoptosis in the TRAIL-/- mice compared to B6 mice. Together, these data strongly suggest that TRAIL plays a role in the control of retinal NV.
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