Anti-Vascular Endothelial Growth Factor Drugs Restore Glial–Vascular Interaction in a Rat Model of Retinopathy of Prematurity

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PURPOSE: Retinopathy of prematurity (ROP), a leading cause of visual impairment and blindness in preterm infants, is characterized by abnormal retinal vascular development, including tortuous arterioles and abnormally dense capillaries. Dysregulated production of vascular endothelial growth factor (VEGF) and disrupted interactions between glial and vascular cells contribute to its pathogenesis. This study investigated the effects of aflibercept, a clinically used anti-VEGF drug, and KRN633, a VEGF receptor tyrosine kinase inhibitor, on abnormal retinal vasculature and astrocyte distribution in a rat model of ROP. METHODS: ROP was induced in neonatal rats by subcutaneous injections of KRN633 on postnatal day (P) 7 and P8. Arteriolar tortuosity, capillary density, mammalian target of rapamycin complex 1 (mTORC1) activity (as indicated by phosphorylation of S6 protein [pS6]), and the distribution of glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated. RESULTS: In ROP model rats, tortuous arterioles and dense capillary plexuses were observed. At the vascular front, many vascular endothelial cells lacked GFAP-positive astrocyte coverage and exhibited strong pS6 immunoreactivity. Treatment with aflibercept or KRN633 significantly reduced capillary density and pS6-positive blood vessels at the vascular front. Following treatment, most vascular endothelial cells were covered by GFAP-positive astrocytes. However, neither aflibercept nor KRN633 ameliorated arteriolar tortuosity. CONCLUSION: These findings suggest that pathological angiogenesis in ROP is mediated through VEGF- and mTORC1-dependent mechanisms. Anti-VEGF therapies may help restore glial-vascular interactions by reducing abnormal blood vessels in the ROP retina.

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