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Sigma 1 Receptor Activation Coordinates Metabolic Stress Responses to Protect Retinal Vasculature in Ischemic
Jing Wang1,2, Xiaowen Lu1,2, Zhengyu Lu1
1Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, United States.
Insights
Activating sigma-1 receptor (Sig1R) protects retinal vasculature in experimental retinopathy of prematurity (ROP). This Sig1R activation preserves vascular integrity and reduces pathological angiogenesis, offering a potential dual neurovascular therapy for ROP vision loss.
Area of Science:
- Ophthalmology
- Vascular Biology
- Neuroprotection
Background:
- Retinopathy of prematurity (ROP) causes vision loss through pathological retinal angiogenesis.
- Current ROP treatments limit neovascularization but don't fully restore vascular function or prevent long-term deficits.
- Sigma-1 receptor (Sig1R) is known for neuroprotection, but its role in retinal vascular protection is unclear.
Purpose of the Study:
- To investigate the potential of Sig1R activation for vascular protection in experimental ROP.
- To determine if Sig1R activation can mitigate pathological angiogenesis and preserve vascular integrity in a mouse model of ROP.
Main Methods:
- Utilized the oxygen-induced retinopathy (OIR) mouse model in wild-type and Sig1R knockout mice.
- Administered (+)-pentazocine ((+)-PTZ) to activate Sig1R systemically.
- Evaluated retinal vascular pathology, barrier integrity, and molecular pathways using angiography, flatmount analysis, immunostaining, and ELISA.
Main Results:
- Sig1R activation by (+)-PTZ restored Sig1R levels, reduced oxidative and inflammatory stress, and suppressed pro-angiogenic factors (VEGF, IL-6, TNF-α).
- Sig1R activation improved retinal vascular barrier integrity, decreased neovascularization, and promoted revascularization of avascular areas.
- These vascular benefits were dependent on Sig1R, as (+)-PTZ had no effect in Sig1R knockout mice.
Conclusions:
- Sig1R activation effectively preserves vascular integrity and suppresses pathological angiogenesis in experimental ROP.
- Sig1R activation demonstrates a dual neurovascular therapeutic potential for ROP.
- Targeting Sig1R offers a promising strategy for treating ROP-associated vision loss.
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.
