Protective effects of rapamycin on the retinal vascular bed during the vaso-obliteration phase in mouse oxygen-induced retinopathy model

Retinopathy of prematurity (ROP) is a vision-threatening disorder characterized with retinal vaso-obliteration in phase 1 and pathological neovascularization (NV) in phase 2. However, there has been no effective and safe treatment for ROP. Current management is mainly focused on the reduction of abnormal NV in phase 2, and anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment, yet, with great risks of late recurrence and systemic side effects. It has been reported that the severity of vaso-obliteration in phase 1 largely influences subsequent NV, suggesting that it may be a promising target to develop novel treatments for ROP. Here, we investigated the therapeutic potential and safety of early rapamycin intervention in treating phase 1 ROP and possible underlying mechanisms using the mouse model of oxygen-induced retinopathy (OIR). We found that intravitreal injection of rapamycin at postnatal day 7 (P7) significantly reduced retinal avascular area, increased vascular density, and reversed the suppression of deep capillaries development in phase 1 of OIR mice. Rapamycin treatment not only reduced vascular apoptosis, but also promoted proliferation and tip cell functions. Additionally, rapamycin did not interfere with normal retinal vascular development. Further investigation showed that Ang1/Tie2 pathway might be involved in rapamycin's vascular protection in phase 1 OIR retinas. Moreover, early rapamycin treatment at P7 had long-term protective effects of reducing retinal NV and avascular area, as well as enhancing vascular maturity in phase 2 of OIR mice. Together, our data suggest that rapamycin may be a safe and promising strategy for early intervention of ROP.