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Elena Ivanova, Botir T Sagdullaev; Targeting hypoxia-inducible factor (HIF) for functional rescue of retinal vasculature in neurodegenerative disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1546.
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© ARVO (1962-2015); The Authors (2016-present)
Controversy exists regarding the fate of retinal blood vessels in rod-originating forms of retinal degeneration. We tested the hypothesis that the survival of blood vessels, blood supply and blood retinal barrier are compromised in rd10 mice, a model of human retinitis pigmentosa and that the function of the blood vessels can be promoted by targeting hypoxia-inducible factor (HIF) in vivo.
First, we determined the density of functional blood vessels, their diameter and integrity of blood retinal barrier at P10, P14, P20, P30, P70, P210 in rd10 mice and wt controls. Freshly enucleated eyes were fixed and immunolabeled for markers of vascular cells and components of the blood brain barrier. To determine contribution of HIF to survival of retinal vasculature in rd10 mice in vivo, we treated mice with Adaptaquin starting from P16. After a weak of daily injections with 40 mg/kg i.p. or topical eye treatments, retinal blood vessels were evaluated.
During progression of photoreceptor degeneration, retinal blood vessels became constricted and progressively degenerated. Degradation of the functional blood vessels was most evident in the deep vascular layer where 70 ± 30% (N = 5 mice) of blood vessels remained at P20 and only 10 ± 5% (N = 5) was present at P210. The superficial layer was least affected. At later stages, outer and inner retinal blood barrier became compromised. To prevent degradation of blood vessels we used Adaptaquin, a potent and selective inhibitor of prolyl hydroxylases enzymes which direct HIF for the proteosomal degradation. The treatment resulted in 44 ± 24% (N = 5) increase of density and a better perfusion of the retinal blood vessels.
Retinal blood vessels become compromised early in retinal degeneration preceding the death of rod and cone photoreceptors. Targeting HIF program promoted survival and function of the retinal blood vessels. Preservation of the blood vessels in retinal degeneration may have therapeutic benefits of extending photoreceptor survival and/or preventing cone secondary death.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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