Intraocular pressure induced blood retinal barrier compromise in mouse models and human glaucoma

The integrity of the blood-retinal barrier remains largely unexplored in glaucoma. Here we show that elevated intraocular pressure partially compromises the blood-retinal barrier in three distinct mouse models of glaucoma. This compromise induces subtle leakage without bleeding or detectable disruption of endothelial cell junctions and precedes neurodegeneration. Leakage occurs from peripheral veins in the retinal ganglion cell layer with a concomitant loss of the transcytosis inhibitor MFSD2A. RNA-sequencing, protein analyses and electron microscopy support enhanced transcytosis as the mechanism for leakage, although a subtle and partial junctional component cannot be ruled out. Importantly, stabilizing β-catenin in retinal endothelial cells prevents both vascular leakage and neurodegeneration. We further detect ganglion cell layer-specific leakage in 14/17 human primary open-angle glaucoma eyes but not in age-matched controls. The high incidence of leakage in mouse models and the human glaucoma eyes suggests that blood-retinal barrier compromise may be a common mechanism of glaucoma.