Dark rearing (dr) as a means of mimicking ‘physiological hypoxia’: rationale for non invasive treatment of retinopathy of prematurity (rop)

"Purpose: ROP is initiated by hyperoxia-induced regression of retinal vasculature via VEGF downregulation. We hypothesized neonates in hyperoxic environments be subject to total darkness, creating a “metabolic sump” to maintain ‘physiological’ expression of VEGF.. Methods: SD rats were raised in: room air+DR from P0-P30; hyperoxic conditions (58%\/72% O2 from P0−4, then returned to room air+normal light) with and without DR and assessed at P7; and under DR\/normal light in the Penn model of ROP. Retinae were examined for vascular density (VDI) & pericyte\/ astrocyte ensheathment and TEM. Functional electroretinograms (fERG) were recorded in long term DR rats (P30\/60\/90). Retinal oxygen profiles were modeled for P14 at 60 and 75% inspired oxygen in light and dark reared conditions.. Results: At P7−14, room air+DR rats had higher vascular density compared to controls (VDI = 43 ± 1.0vs.38 ± 1.1 p < 0.05). DR protects vessels from oxygen-induced vaso-obliteration & preserves normal mural cell ensheathment in 58% O2 (29 ± 1.1vs.28 ±. 1.3 p > 0.05) but is overwhelmed in 72% O2 (29 ± 1.1vs.23 ± 0.66 p < 0.05) after 4 days of hyperoxia from P0. DR is neuroprotective in the Penn model and long term DR has no detrimental effects on retinal cell morphology, as evidenced by TEM and fERG. Oxygen consumption modeling at P14 showed that at ∼58% inspired oxygen, the inner retina is hypoxic, maintaining VEGF expression in darkness, but not in light.. Conclusion: We showed that DR precludes the initiating event in ROP, offering a non-invasive intervention. This is timely, given the enthusiasm for clinical adoption of anti-VEGF therapy, where possible systemic toxicity has not been fully investigated. "