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Edith Aguilar, Ayumi Ouchi, Yoshihiko Usui, Toshihide Kurihara, Michael Dorrell, Yoichiro Ideguchi, Martin Friedlander; Role of microglia in the formation of subretinal neovascularization in Vldlr-/- mice. Invest. Ophthalmol. Vis. Sci. 2020;61(7):5403.
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© ARVO (1962-2015); The Authors (2016-present)
Subretinal neovascularization (NV) is a central characteristic of vision-threatening retinal diseases including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). However, further understanding of the pathogenesis and formation of subretinal NV is required. The very low density lipoprotein receptor knockout mouse (Vldlr-/-) models key vascular anomalies of these diseases. We have shown that retinal microglia closely associate with retinal neovascular tufts in Vldlr-/- mice, preceding areas of subretinal NV and that a reduction of retinal myeloid cells using an M-CSF inhibitor reduces NV tuft formation and protects visual function. Here we further confirm a critical role for activated microglia in promoting subretinal NV in Vldlr-/-mice and investigate the mechanism of retinal microglia-induced subretinal NV.
Retinal microglia / macrophages were selectively ablated in Vldlr-/- mice using Cx3cr1 Cre-ERT; Rosa26iDTR/+; Vldlr-/- mice where a transgene encoding a human diphtheria toxin receptor (iDTR) is activated by Cx3cr1-expressing cells (microglia / macrophages). The effects on NV tufts were analyzed and compared with control littermates as well as Vldlr-/- mice with retinal microglia activated by LPS injection. Finally, we analyzed the role of microglia-derived vs. RPE-derived VEGF in activation of retinal microglia and retinal tuft formation using Cx3Cr1-Cre; Vegfaf/f or LysM-Cre; Vegfaf/f mice in the Vldlr-/- background to specifically knock-down VEGF in microglia, and VMD2Cre; Vegfaf/f; Vldlr-/- mice to specifically knock-down VEGF in RPE.
Genetic ablation of retinal microglia/macrophages in Vldlr-/- mice resulted in a significant reduction of retinal NV tufts to 25% of control levels. In contrast, activation of microglia resulted in a 250% increase in NV tuft formation when LPS was injected prior to NV formation, but did not further increase NV when injected after normal tuft formation. While microglia-derived VEGF did not contribute to subretinal NV, RPE-derived VEGF activated retinal microglia and subsequently increasing subretinal NV tuft formation.
Activation of retinal microglia by RPE-derived VEGF plays a critical role in the formation of subretinal NV in the Vldlr-/- mouse. These results suggest that microglia may be a viable target for treatment of diseases such as MacTel and RAP.
This is a 2020 ARVO Annual Meeting abstract.
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