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Gaëlle Mawambo, Agnieszka Dejda, Khalil Miloudi, Przemyslaw (Mike) Sapieha; Myeloid cell ER-stress contributes to pathological retinal neovascularisation in ischemic retinopathy.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3643.
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© ARVO (1962-2015); The Authors (2016-present)
Proliferative ischemic retinopathies such as proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) are the principal causes of vision loss in working age and pediatric populations of industrialized countries. We recently showed the critical role for a subset of myeloid-derived mononuclear phagocytes in pathological pre-retinal angiogenesis. One cellular manifestation of hypoxia/ischemia is the induction of endoplasmic reticulum (ER) stress, specially the IRE1α branch which has been implicated in retinopathy. Here we investigated the role of myeloid cell-resident IRE1α in the development of ocular pathological angiogenesis.
We generated transgenic mice with IRE1α deleted specifically in myeloid cells by breading LyzMcre mice with Ire1α floxed mice. Mouse pups (C57B/L6 or LyzMcre Ire1α+l+ as controls and LyzMcre Ire1α fl/fl) and their mothers were exposed to 75% O2 from P7 to P12 and returned to room air. We enucleated eyes at postnatal days 12 (P12), and 17(P17) and dissected retinas. Isolated retinas were flat mounted and incubated overnight with isolectin B4 to determine extent of avascular area or neovascularization area at P17 using ImageJ and SWIFT-NV.
Upon exit from 75% O2 at P12, there was no difference in extent of retinal vaso-obliteration in LyzMcre Ire1α fl/fl mice when compared to C57B/L6 and LyzMcre Ire1α+l+ controls. Importantly, at P17, when pathological neovascularization peaks, deletion of myeloid-resident IRE1α profoundly reduced avascular areas (~30% when compared with C57B/L6 and with LyzMcre Ire1α+l+ mice). In turn, we observed a significant reduction in destructive retinal neovascularization associated with ischemic retinopathy (~40% when compared with C57B/L6 and ~30% compared with LyzMcre Ire1α+l+ mice).
Cell-specific knockout of IRE1α in the myeloid cell lineage reduces pathological retinal angiogenesis. These findings contribute to elucidating the growing link between ER-stress and angiogenesis, and suggest that targeting pathways of ER-stress such as IRE1α may offer alternative treatment strategies for vision threatening ocular vascular diseases.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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