Nitro-Oleic acid protects from neovascularization, oxidative stress, gliosis and neurodegeneration in oxygen-induced retinopathy

Inflammation and oxidative stress are involved in Proliferative Retinopathies (PR). Müller glial cells (MGCs) and microglia play pivotal roles in pathological neovascularization (NV) and neurodegeneration in PR. Nitro-fatty acids are important electrophilic signaling mediators with anti-inflammatory and antioxidant properties. Herein, our goal was to evaluate the cytoprotective effect of nitro-oleic acid (NO₂-OA) on neurons, MGCs and microglia in a mouse model of oxygen-induced retinopathy (OIR). NO₂-OA induced vascular regrowth and reduced NV at P17 OIR, although no difference in the proangiogenic/antiangiogenic (VEGF-A/PEDF) balance was found between NO₂-OA treatment and vehicle. In addition, Western blot and immunofluorescence assays showed that NO₂-OA prevented gliosis at P17 OIR and decreased the number and activation of IBA1+ retinal myeloid cells. However, NO₂-OA did not restore the decrease in expression of glutamine synthase (GS). Loss of retinal function in OIR mouse model measured by electroretinography was ameliorated, mainly at P26 OIR, after NO₂-OA treatment. Western blot analysis of retinas from OIR mice revealed decreased levels of caspase-3 protein and increased number of TUNEL-positive cells at P26 compared to RA. Notably, these alterations were partially prevented after NO₂-OA treatment. Besides, NO₂-OA attenuates oxidative stress induced in MGCs exposed to aqueous humor from patients with different stages of PR. These findings highlight NO₂-OA as a promising therapeutic strategy targeting both vascular and neuroglial components in PR, suggesting its potential clinical relevance.