Microglia Drive Peripapillary Vascular Density Reduction in Normal Tension Glaucoma by Regulating the Rpl17/Stat5b/Apoa1 Axis

Normal tension glaucoma (NTG) is a predominant subset of glaucoma in Asia and is characterized by glaucomatous optic neuropathy in the absence of elevated intraocular pressure. Alterations in retinal blood vessels are reported to be important mechanisms of glaucomatous optic nerve damage. Retinal peripapillary vascular density is assessed in patients with early stage NTG and OPTN (E50K) mutant mice and confirmed a similar reduction in retinal peripapillary vascular density in patients with NTG and model mice. Thus, identifying the mechanisms underlying retinal vascular changes in NTG is crucial for developing effective therapeutic strategies. This study revealed that Rpl17 is upregulated in the retinal microglia of OPTN (E50K) mutant mice. Rpl17 exerts regulatory control over Apoa1 by directly interacting with Stat5b, which causes damage to retinal vascular endothelial cells and leads to a reduction in retinal peripapillary vascular density. Additionally, we identified ellagic acid (EA) as an Apoa1 antagonist that is able to alleviate damage to retinal vascular endothelial cells and increase retinal peripapillary vascular density, which subsequently protected retinal ganglion cells and improved visual function. The work elucidates the vascular mechanism of NTG optic nerve damage and proposes EA as an effective adjuvant therapy strategy.