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A. J. Stempel, M. H. Davies, K. E. Hubert, D. Williamson, H. You, G. Thomas, M. R. Powers; Modulation of the Extrinsic Pathway of Apoptosis Alters Neovascular Regression in the Mouse Model of Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4485.
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Our laboratory has demonstrated that the extrinsic pathway of apoptosis plays an important role in controlling retinal neovascularization (NV) in oxygen-induced retinopathy (OIR). PACS-2, a multi-functional cell sorting protein, specifically contributes to TRAIL-induced apoptosis by mediating Bid translocation and cleavage (truncated Bid). We used PACS-2 deficient (-/-) mice to determine if the tBid amplification step contributes to the proapoptotic control of retinal NV during retinal development and ischemia-induced retinopathy.
Retinal vascular development was analyzed in PACS-2-/- and C57BL/6 (B6) mice at P5 and P7 using lectin-labeled whole mounts. PACS-2-/- and B6 mice were exposed to 75% oxygen from postnatal day 7 (P7) to P12 and recovered in room air. Retinal PACS-2 expression was evaluated in room air and hyperoxia exposed B6 mice by RT-PCR. Retinal vaso-obliteration was quantified from lectin-labeled retinas at P12. NV was quantified from H&E stained cross-sections from P17, P21, and P24 retinas. Qualitative analysis of retinal vascularization was performed in lectin-labeled retinal whole mounts from P12, P17, and P21.
PACS-2-/- mice had normal retinal development at P5 and P7 compared to B6. PACS-2 mRNA was expressed in both room air and hyperoxia exposed B6 retinas at P17, P21, and P24. Upon removal from hyperoxia at P12, 45.9±1.1% of the retina was avascular in PACS-2-/- mice compared to 32.5±1.2% in B6 mice (p<0.0001; n=6-8). At P17 after hyperoxia exposure, there was no significant difference in NV between PACS-2-/- (18.6±4.1 neovascular nuclei per section) and B6 (25.1±1.2; p=0.07; n=5-10 eyes) mice. However, a significant increase in retinal NV was observed at P21 after hyperoxia exposure between PACS-2-/- mice (30.8±7.2) compared to B6 mice (9.8±2.5; p=0.0087; n=8-10). At P24, the PACS-2-/- mice continued to exhibit a significantly delayed neovascular regression, with 21.15 ± 5.59 preretinal neovascular nuclei as compared to 3.09 ± 0.82 in controls (p=0.0002, n=6-10).
Both the vaso-obliterative and neovascular phases of OIR are altered in PACS-2-/- mice. The delayed regression of NV seen at P21 and P24 in PACS-2-/- mice provides additional evidence that proapoptotic TRAIL plays a role in the control of retinal NV. These results demonstrate the critical role that mitochondrial amplification of the extrinsic apoptosis pathway plays in regression of pathologic neovascularization.
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