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Maya Barben, Christian Schori, Christian Grimm, Marijana Samardzija; HIF1A is the responsible factor for cone degeneration and subretinal neovascularization in a mouse model of chronic hypoxia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):965. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Numerous factors have been proposed and/or validated to contribute to the development and progression of age-related macular degeneration (AMD). An important factor in AMD pathology might be reduced retinal oxygenation. Age-related changes in the cone-rich macula may limit oxygen supply and lead to chronic hypoxia, which triggers several cellular mechanisms orchestrated by hypoxia-inducible factors (HIFs). Here, we activated a chronic hypoxic response in the all-cone mouse and studied the contribution of HIFs on cone pathophysiology.
We deleted the von Hippel Lindau (VHL) protein specifically from cone photoreceptors of all-cone (R91W;Nrl-/-) mice and analyzed the resulting BPCre;R91W;Nrl-/-;Vhlf/f (=coneΔVhl) mice at different time-points between 11 days and 26 weeks of age. Littermates without the Cre recombinase served as controls. Retinal function and morphology were evaluated by ERG and microscopy. Transcriptomic analysis and Western blotting were used to analyze the molecular response. To investigate the impact of HIF1A on the phenotype, we deleted Hif1a in cone photoreceptors of coneΔVhl mice.
Cone-specific Vhl deletion resulted in HIF1A stabilization in coneΔVhl mice and increased expression of HIF1A target genes involved in, among others, energy metabolism and mitophagy. Reduced retinal function and decreased thickness of the outer nuclear layer indicated progressive cone degeneration. Additionally, we observed neovascularization with vessels extending from the deep plexus into the photoreceptor layer. Additional deletion of Hif1a prevented cone photoreceptor loss and pathological vessel growth without affecting developmental formation of the three retinal vascular plexi.
Chronic activation of HIF transcription factors in cone photoreceptors of the all-cone retina led to subretinal neovascularization and cone degeneration, features that are central to a distinct form of AMD known as retinal angiomatous proliferation (RAP). Our data provide evidence that the observed phenotype in coneΔVhl mice is HIF1-dependent, as additional deletion of Hif1a fully rescued the phenotype. Hence, we suggest that cell type-specific targeting of HIF1A might be a potential strategy to rescue vision in hypoxia-mediated retinal degenerative diseases.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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