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D.A. Rewolinski, C.G. Grove, M.N. Cobbs, J.H. Goldman, M.R. Niesman; A Potent and Selective Inhibitor of VEGFR and PDGFR Inhibits Ocular Angiogenesis . Invest. Ophthalmol. Vis. Sci. 2005;46(13):469.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To evaluate ocular angiogenesis following treatment with AG–013958, a potent inhibitor of the kinase domain of both VEGFR and PDGFR, in models of rat retinal vascular development and neovascularization. Methods: In a model examining normal rat retinal vascular development, AG–013958 was administered both by intraperitoneal and intravitreal injection. Compound was administered to either postnatal (P) day 6, 8, or adult Sprague–Dawley rats. In the rat hyperoxia/hypoxia model of retinopathy of prematurity (ROP), AG–013958 was administered by intravitreal injection following the animal’s return to room air. At sacrifice, retinas were removed for either histochemical analysis by staining for ADPase activity or analysis of receptor phosphorylation. Results: Retinas from animals treated at P8, either by intraperitoneal or intravitreal injection, showed inhibition of vasculature development and regression of previously developed capillaries when compared to vehicle treated animals. There was no difference in the retinal vasculature between control and treated retinas in the adult animals. In the ROP model, treated animals showed inhibition of retinal neovascularization when compared to vehicle treated animals. P6 animals treated with compound by intraperitoneal injection also showed inhibition of VEGFR–2 phosphorylation.Conclusions:AG–013958 inhibited rat retinal vasculature development and pathologic neovascularization. Furthermore, AG–013958 induced capillary regression during normal retinal vascular development. This regression appears to be mediated by inhibition of VEGF receptor signaling at a time when VEGF is thought to provide an angiogenic stimulus and act as a survival factor for capillaries in retina.
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