Systemic rapamycin inhibits retinal and choroidalneovascularization in mice

[摘要] Purpose: Rapamycin exhibits significant antitumor/antiangiogenicactivity that is coupled with a decrease in vascular endothelial growthfactor (VEGF) production and a reduction in the response of vascularendothelial cells to stimulation by VEGF. VEGF plays a significant rolein neovascular pathologies of the eye, thus we tested the possibility ofusing rapamycin to inhibit retinal and choroidal neovascularization(CNV).Methods: CNV was induced in adult mice with laser photocoagulation.Retinal neovascularization was induced using the retinopathy ofprematurity (ROP) hyperoxia/hypoxia model. Experimental animals receivedintraperitoneal (ip) injections of rapamycin (2 mg/kg/day or 4mg/kg/day) for 1-2 weeks. Controls were not treated or received ipinjections of phosphate buffered saline (PBS). Eyes were analyzedhistologically for evidence of CNV or retinal neovascularization. ROPeyes were further analyzed for changes in VEGF and VEGF receptor (Flt-1and Flk-1) protein content following rapamycin treatment.Results: Rapamycin significantly reduced the extent ofneovascularization in both the CNV and the ROP model.Immunohistochemical staining of treated and untreated ROP retina did notreveal a significant reduction in levels of VEGF protein or itsreceptors. Immunostaining for Flt-1 increased, while no obvious changesin Flk-1 were observed. Quantitative analysis of total protein viaenzyme linked immunosorbent assay (ELISA) confirmed an increase in Flt-1and VEGF, following drug treatment, with no effect on Flk-1.Conclusions: These results suggest rapamycin may provide aneffective new treatment for ocular neovascularization.

[学科分类] 生物化学/生物物理