Systemic rapamycin inhibits retinal and choroidal neovascularization in mice

• Published in: Molecular vision 2004-12, Vol.10, p.964-972
• Main Authors: Dejneka, Nadine S, Kuroki, Akiko M, Fosnot, Joshua, Tang, Waixing, Tolentino, Michael J, Bennett, Jean
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Choroid - drug effects; Choroid - metabolism; Choroid - pathology; Choroidal Neovascularization - drug therapy; Choroidal Neovascularization - metabolism; Choroidal Neovascularization - pathology; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Fluorescent Antibody Technique, Indirect; Immunosuppressive Agents - therapeutic use; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Myosin Heavy Chains; Nonmuscle Myosin Type IIB; Proteins - metabolism; Retina - drug effects; Retina - metabolism; Retina - pathology; Retinal Neovascularization - drug therapy; Retinal Neovascularization - metabolism; Retinal Neovascularization - pathology; Sirolimus - therapeutic use; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 1090-0535

Rapamycin exhibits significant antitumor/antiangiogenic activity that is coupled with a decrease in vascular endothelial growth factor (VEGF) production and a reduction in the response of vascular endothelial cells to stimulation by VEGF. VEGF plays a significant role in neovascular pathologies of the eye, thus we tested the possibility of using rapamycin to inhibit retinal and choroidal neovascularization (CNV). CNV was induced in adult mice with laser photocoagulation. Retinal neovascularization was induced using the retinopathy of prematurity (ROP) hyperoxia/hypoxia model. Experimental animals received intraperitoneal (ip) injections of rapamycin (2 mg/kg/day or 4 mg/kg/day) for 1-2 weeks. Controls were not treated or received ip injections of phosphate buffered saline (PBS). Eyes were analyzed histologically for evidence of CNV or retinal neovascularization. ROP eyes were further analyzed for changes in VEGF and VEGF receptor (Flt-1 and Flk-1) protein content following rapamycin treatment. Rapamycin significantly reduced the extent of neovascularization in both the CNV and the ROP model. Immunohistochemical staining of treated and untreated ROP retina did not reveal a significant reduction in levels of VEGF protein or its receptors. Immunostaining for Flt-1 increased, while no obvious changes in Flk-1 were observed. Quantitative analysis of total protein via enzyme linked immunosorbent assay (ELISA) confirmed an increase in Flt-1 and VEGF, following drug treatment, with no effect on Flk-1. These results suggest rapamycin may provide an effective new treatment for ocular neovascularization.