Abstract
Purpose :
Retinal neovascularization (NV) represents a common hallmark of retinal ischemic diseases in the context of diabetes or retinal vascular occlusion. While hypoxia is known to be a main driver of vascular endothelial cell proliferation and retinal neovascularization, it becomes more apparent that the inflammatory microenvironment and associated signaling pathways modulate hypoxia driven angiogenesis. In this study, we analyze the effect of Oncostatin M (OSM), a strong STAT3 activator with well-documented pro-angiogenic properties outside the eye, in a mouse model of hypoxia-induced retinopathy.
Methods :
In the mouse model of oxygen-induced retinopathy (OIR) Bl6/J pups were subjected to hyperoxia between postnatal day (P) 7 and 12. Upon return to room air at P12 mice received intravitreal injections with 0.5µL of 100ng/µl OSM or PBS control. Retinal vascular phenotype following treatment was quantified at P17. Western blot analysis and immunohistochemical stainings on retinal cryosections for pSTAT3 were performed 12h post injection. Retinal vascular endothelial cells were isolated at P17 via cell sort using a CD31+/CD45- gating strategy and submitted for RNA sequencing.
Results :
OSM reduced retinal NV in the OIR model by 65,2% compared to PBS-treated controls (N=11 mice, p<0.05). Western blot analysis showed a clear increase in pSTAT3 levels in retinal lysates 12 h post treatment. Immunohistochemical analysis visualized a positive pSTAT3 signal in the inner nuclear layer as well as GFAP upregulation in Müller cells suggesting a primary Müller cell response to OSM treatment. RNA sequencing of sorted vascular endothelial cells at OIR P17 revealed a downregulated angiogenic profile following OSM treatment (GSEA: GO angiogenesis, enrichment score 0.287 p<0.05).
Conclusions :
OSM possesses therapeutic potential by a primary activation of Müller cells resulting in downregulation of angiogenic drivers in vascular endothelial cells.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.