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Tailoi Chan-Ling, Samuel Adamson, Riccardo Natoli, Rita Maccarone, Mark Koina, Ping Hu, Jennifer C Lau, Jan M Provis, Robert A Linsenmeier, Silvia Bisti; Dark-Rearing (DR) Mitigates Pre-Retinal Neovascularization and OIR Pathology with no Detriment To Visual Function and Morphology: Compelling Evidence For DR as Non-Invasive Intervention in Retinopathy of Prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2014;55(13):5902.
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ROP is initiated by hyperoxia-induced down-regulation of VEGF expression. We hypothesized that the initiating event in ROP can be blocked by subjecting neonates to total darkness, during the period O2 exposure is required to protect vital organs, as darkness results in continuous depolarization of photoreceptors, requiring energy (O2) intensive repolarisation.
SD rats were raised in: 21% O2 + dark rearing (DR) from P0-30; hyperoxic conditions (60%/70% O2 from P0-4, returned to 21% O2 + normal light) with and without DR & assessed at P7; & under DR/normal light in 50/10 OIR & assessed at P18. Retinae were examined for vascular density (VDI), extent of peripheral vaso-obliteration & neovascularization, pericyte/astrocyte ensheathment and ultrastructural changes via TEM. Flash electroretinograms (fERG) were recorded in both 30 days post 50/10 OIR, & in long term DR rats (P30/60/90). Retinal O2 profiles were modeled for P14 at 60 & 75% inspired O2 in light & DR.
We showed DR rats had higher VDI compared to age-matched controls (VDI=43±1.0 vs.38±1.1 p<0.05 - P7). DR protected vessels from O2-induced peripheral vaso-obliteration (20.64% ± 4.85 v 39.02% ± 4.03 p<0.05) and reduced areas of pathological neovascularization (4.07% ± 0.85 v 15.79% ± 1.26 p<0.05) in 50/10 OIR. DR protects vessels from O2-induced vaso-obliteration without harmful effects on normal microvascular cell interactions (as evidenced by normal astrocytic and pericytic ensheathement); retinal cell morphology as evidenced by TEM; & function as evidenced by fERG at 30 days post OIR, & after 90 days continuous DR. For all groups, average b-wave amplitudes from DR rats v dark/light cycle rats were not significantly different. O2 profile modelling under DR at 60% inspired O2 at P14 showed that the inner retina maintains 'physiological hypoxia', in darkness but not in light whilst 75% inspired O2 overwhelms the protective effect of DR.
We showed that DR precludes the initiation in experimental models of ROP, offering a viable, non-invasive intervention. DR could be utilized in combinational therapy to minimise the damaging effect of ROP in infants. This is timely, given current clinical use of anti-VEGF therapy for ROP, where long-term systemic effects have not been fully investigated.
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