| First Author | Xu Z | Year | 2025 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 45 |
| Issue | 11 | Pages | e544-e562 |
| PubMed ID | 40964715 | Mgi Jnum | J:377266 |
| Mgi Id | MGI:8273804 | Doi | 10.1161/ATVBAHA.125.323301 |
| Citation | Xu Z, et al. (2025) Nrf2 Deficiency in Muller Cells Exacerbates Pathological Neovascularization in Ischemic Retinopathy. Arterioscler Thromb Vasc Biol 45(11):e544-e562 |
| abstractText | BACKGROUND: Muller cells are the major retinal glial cell type and pivotal regulators of pathological neovascularization in ischemic retinopathy. There is great interest in identifying factors that govern Muller cells in vascular regulation. Nrf2 (NF-E2-related factor 2) plays a major protective role in regulating oxidative stress and inflammation. Our group previously discovered that both global and neuroretinal Nrf2 deficiency suppress retinal revascularization and promote pathological neovascularization in a mouse model of oxygen-induced retinopathy. Here, we investigate the cell-intrinsic role of Nrf2 in Muller cells on retinal angiogenesis. METHODS: The role of Muller cell Nrf2 in retinal angiogenesis was investigated in cell culture and the mouse oxygen-induced retinopathy model. Human retinal endothelial cells were cocultured with primary Muller cells transfected with Nrf2 small-interference RNA. Muller cell-specific Nrf2 knockout mice were subjected to oxygen-induced retinopathy. RNA-seq analysis of a Muller cell-specific RiboTag transcriptome was conducted in wild-type and Nrf2-deficient Muller cells. RESULTS: Silencing Nrf2 in primary Muller cells increased angiogenic activity in retinal endothelial cells. Muller cell-specific Nrf2 deficiency exacerbated pathological neovascularization in oxygen-induced retinopathy, associated with increased Muller cell gliosis and upregulation of retinal Tnfalpha (tumor necrosis factor alpha). Muller cell Nrf2 deficiency resulted in dysregulation of multiple genes involved in acute-phase response, inflammation, and angiogenesis, including increased expression of Lcn2 (lipocalin-2) and Fgf2, both of which promoted angiogenesis in human retinal endothelial cells. Blocking LCN2 with a neutralizing antibody attenuated pathological neovascularization and vaso-obliteration, suggesting LCN2 is a key mediator of aberrant angiogenic response in Muller cell-specific Nrf2 deficiency. CONCLUSIONS: Nrf2 in Muller cells plays an integral protective role in modulating retinal angiogenesis and inflammatory responses in ischemic retinopathy. Nrf2 is an important regulator of Muller cell state in retinal ischemia and governs the Muller cell transcriptional program, including LCN2, a novel regulator of angiogenesis. This highlights pharmacological activation of Nrf2 as a therapeutic strategy for pathological neovascularization in ischemic retinopathy. |
