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Alison Chu, Michel Sun, David Casero, Lynn Gordon, Madhuri Wadehra; Targeting epithelial membrane protein-2 in retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1652.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) remains a significant contributor to late neurodevelopmental morbidity in premature infants, and the role of inflammation and immune cell recruitment in the neovascularization phase of disease remains poorly understood. Epithelial membrane protein-2 (EMP2) is a tetraspan membrane protein that has been described in cancer and reproductive disease to regulate angiogenesis as well as immune cell recruitment. In this study, we tested the hypothesis that EMP2 contributes to the neovascularization phase of ROP using a murine model.
We subjected wild-type and EMP2 knock-out mice to hyperoxia (75% oxygen concentration) or normoxia (21% oxygen concentration) during postnatal (p) days 7-12 (n=6-10 mice/group). Following euthanasia, eyes were collected at various time points from p12-p17 for whole mount evaluation and retinal/choroidal RNA transcriptomic analysis. Lectin was used to identify the vasculature and the samples were evaluated for the degree of vasoobliteration at p12 and vasoproliferation at p17. RNA sequencing was used to identify transcriptomic differences between WT and EMP2 KO under hyperoxic and normoxic conditions. Statistical analyses were performed using Student’s t-test or ANOVA.
Following hyperoxia, decreased neovasculatization at p17 was observed in the EMP2 KO animals as compared to WT (WT: 1±0.164 fold change; EMP2: 0.724±0.156; p=0.008) but not vasoobliteration at p12 (WT: 1±0.143 FC; EMP2: 1.058±0.078 FC; p=0.277). Under normoxic conditions, significant retinal transcriptomic differences were not detected between the WT and EMP2 KO p17 pups. However, under hyperoxia conditions for both genotypes, significant transcriptional functional pathway changes, as anticipated, occurred in angiogenesis and oxidative stress pathways. In comparison to normoxia the hyperoxic exposed EMP2 KO animals differentially expressed ~1000 genes, in contrast to ~700 genes in the WT. Under hyperoxic conditions, in comparison to the WT, EMP KO animals exhibited greater amplification in myeloid cell recruitment and apoptotic signaling pathways.
EMP2 expression may exacerbate the neovascularization phase of ROP using a murine model of oxygen-induced retinopathythrough upregulation of apoptotic signaling and myelioid cell recuitment. Additional studies will further define the role for potential therapeutic interventions through EMP2 in pathologic neovascularization.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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