Chronic intermittent hypoxia disrupts protective microgliosis in ischemic proliferative retinopathy

Abstract Sleep apnea that leads to chronic intermittent hypoxia (CIH) is an independent risk factor for advanced, debilitating ischemic proliferative retinopathies, such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP). The underlying mechanisms are unknown. Here we investigated the consequences of CIH on the ischemic retina of the oxygen-induced retinopathy model. We show that experimental CIH inhibited colony stimulating factor 1 (CSF1) expression, blunting the reactive microgliosis during the ischemic phase of OIR. CIH severely delayed beneficial revascularization of the ischemic retina and increased pathological neovascularization. CIH also induced photoreceptor segment thinning and accentuated OIR-induced inner and outer retinal functional deficits. Mechanistically we demonstrated that local CSF1R inhibition during ischemic retinopathy reduced the number of microglial cells, inhibited revascularization, and exacerbated pathological neovascularization, recapitulating the 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 DR and ROP to help prevent sight threatening severe disease.