The Inability of the Choroid to Revascularize in Oxygen-Induced Retinopathy Results from Increased p53/miR-Let-7b...

Area of Science:

• Ophthalmology
• Molecular Biology
• Developmental Biology

Background:

• Retinopathy of prematurity (ROP) involves retinal neovascularization and is now linked to choroidal thinning.
• The mechanisms behind impaired choroidal revascularization in ROP remain poorly understood.
• Oxygen-induced retinopathy (OIR) models exhibit choroidal thinning, offering a platform to study these mechanisms.

Purpose of the Study:

• To investigate the molecular mechanisms underlying defective choroidal revascularization in an oxygen-induced retinopathy (OIR) model.
• To identify key factors and pathways involved in maintaining choroidal integrity during OIR.

Main Methods:

• Utilized an oxygen-induced retinopathy (OIR) mouse model.
• Assessed senescence, oxidative stress, and gene/miRNA expression in retinal and choroidal tissues.
• Manipulated p53 activity and let-7b expression, and measured insulin-like growth factor 1 receptor (Igf1R) levels.
• Evaluated choroidal thickness and revascularization.

Main Results:

• OIR induced senescence, oxidative stress, and reduced proangiogenic Igf1R expression in the choroid and retinal pigment epithelium.
• Elevated p53 expression correlated with decreased Igf1R and choroidal thinning.
• Inhibition of p53 reversed senescence, normalized Igf1R, and preserved choroidal integrity.
• OIR upregulated miR-let-7b, which directly targeted Igf1R mRNA; p53 inhibition blunted let-7b, restored Igf1R, and promoted choroidal revascularization.
• Restoring Igf1R expression rescued choroid thickness.

Conclusions:

• A novel p53/let-7b/IGF-1R signaling axis significantly impacts choroidal revascularization in OIR.
• This pathway is critical for maintaining choroidal integrity and may be a therapeutic target for ROP.
• Findings may also inform understanding of other degenerative choroidopathies like geographic atrophy.