Intraocular Gutless Adenoviral-Vectored VEGF; A Model of Anterior Segment Neovascularization (NV)

Abstract

Abstract: : Purpose: Vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) have been implicated as important stimulatory factors for retinal neovascularization. In this study, we used intraocular gene transfer with gutless adenoviral (AGV) vectors to determine the effect of increased intraocular expression of VEGF, IGF-1, or sphingosine kinase (SPK), which produces sphingosine-1-phosphate, another angiogenic factor. Methods:Adult C57BL/6 mice were given intravitreous injection one of following: AGV-VEGF, AGV-IGF1, AGV-SPK. On days 7, 14, 21, and 28 after injection, anterior segment NV and retinal NV were assessed by biomicroscopy and image analysis of corneal flat mounts from mice perfused with fluorescein-labeled dextran. Results: Retinal NV did not occur from intravitreous AGV-vectored VEGF, IGF-1, SPK, or combined VEGF and IGF-1, except occasionally adjacent to the retinal penetration site from the injection. However, corneal and iris NV occurred after two weeks in all eyes injected with AGV-VEGF, but not those injected with only AGV-IGF-1 or AGV-SPK. Conclusions: These data suggest that the superficial capillary bed of the retina is relatively insensitive to VEGF, IGF-1, or SPK in adult mice, except when combined with retinal trauma. However, AGV-vectored VEGF is sufficient to consistently cause severe corneal and iris neovascularization. This provides a new model for anterior segment NV, which unlike previous models is relatively inexpensive, is not plagued by spontaneous regression, and may be useful for identification of new treatments.

Keywords: animal model • gene transfer/gene therapy • neovascularization