Sigma 1 Receptor Activation Coordinates Metabolic Stress Responses to Protect Retinal Vasculature in Ischemic Retinopathy

Purpose: Retinopathy of prematurity (ROP)-associated vision loss is driven by pathological retinal angiogenesis. Current therapies suppress neovascularization but do not fully restore vascular integrity or prevent long-term visual deficit. Activation of the sigma-1 receptor (Sig1R) has been reported to confer neuroprotection, yet its role in retinal vascular protection remains largely unexplored. Here, we investigated whether Sig1R activation confers vascular protection in experimental ROP. Methods: The oxygen-induced retinopathy (OIR) mouse model was induced in wild-type and Sig1R-/- mice with or without systemic (+)-pentazocine ([+]-PTZ) administration to activate Sig1R. Retinal vascular pathology, barrier integrity, and avascular areas were evaluated by fluorescein angiography and retinal flatmount analysis. Molecular changes in metabolic, oxidative, and inflammatory pathways were assessed by immunostaining/blotting and ELISA assay. Results: Sig1R expression was reduced in OIR retinas, accompanied by decreased cullin-3 ubiquitin ligase (Cul3) and phosphorylated AMP-activated protein kinase (pAMPK) and increased pAkt and endothelial nitric oxide synthase (eNOS), indicative of metabolic and endothelial stress. Activation of Sig1R with (+)-PTZ restored Sig1R, Cul3, and pAMPK levels, suppressed pAkt/eNOS signaling, reduced oxidative stress, and attenuated Müller glial activation. OIR-induced upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and pro-angiogenic/inflammatory mediators, including vascular endothelial growth factor (VEGF), IL-6, TNF-α, macrophage colony-stimulating factor (M-CSF), vascular cell adhesion molecule 1 (VCAM-1), and tumor necrosis factor receptor (TNFR), were markedly reduced by (+)-PTZ. Functionally, Sig1R activation improved retinal vascular barrier integrity, reduced arterial tortuosity and pathological neovascularization, and promoted revascularization of avascular retina. Importantly, (+)-PTZ treatment failed to confer any vascular benefit in Sig1R-/- mice, confirming that these vascular benefits are Sig1R dependent. Conclusions: Sig1R activation preserves vascular integrity and suppresses pathological angiogenesis in OIR. Together with known neuroprotective effects, Sig1R represents a promising dual neurovascular therapeutic target for ROP.