Chronic intermittent hypoxia inhibits the revascularization of the ischemic retina and aggravates neurodegeneration and neovascularization

Neovascular retinopathies and edema are sign threatening complications of ischemic retinopathies, such as retinopathy of prematurity (ROP) and diabetic retinopathy (DR). Sleep apnea that leads to chronic intermittent hypoxia (CIH) is an independent risk factor for severe disease, but the underlying mechanisms are unknown. Here we show that experimental CIH during the ischemic phase of oxygen induced retinopathy in mice severely reduces beneficial revascularitzation of the ischemic retina, and increases neuronal loss and pathological neovascularization. Mechanistically we demonstrate that CIH reduces both colony stimulation factor 1 (CSF-1) expression and the ischemia-induced increase of retinal microglial cells that promotes the revascularization of the ischemic retina in the absence of CIH. Local CSF1R inhibition during ischemic retinopathy reduced the number of microglial cells, inhibited revascularization, and exacerbated pathological neovascularization, recapitulating several effects of CIH. Our findings provide a novel mechanism by which sleep apnea and CIH aggravate ischemic retinopathies, underscoring the importance of treating apnea in ROP and DR to help prevent sight threatening severe disease. C57BL/6J mice at postnatal (PN) day 8 (PN8) were exposed, with their mothers, for 5 days to hyperoxic conditions (75% O2), inducing vaso-obliteration and subsequent capillary loss of the central retinal vasculature known as oxygen-induced retinopathy (OIR). At PN13, mice were returned to room-air conditions which induces extensive neovascularization in all experimental mice with maximum effects on PN18 (group named OIR-Norm), or were placed in chronic intermittend hypoxia (CIH) conditions (group named OIR-CIH). Control animals (OIR-Norm) were exposed to the same flow (and noise) of gasses, without affecting O2 concentrations. Fresh eyes (3 eyes from the OIR-Norm group, 3 eyes from the OIR-CIH group, all at PN18) were dissected on ice to isolate retinas immediately after enucleation. Retinal RNA was extracted and bulk RNA sequencing was performed. OIR-Norm samples are controls and OIR-CIH samples are the experimental condition.