Insulin-like growth factor-1 retinal microangiopathy in the pig eye

Human recombinant insulin-like growth factor-1 (hrIGF-1), a ubiquitous angiogenic growth factor, was injected into the vitreous cavity of pigs to investigate the clinical and histopathologic consequences of supraphysiologic levels of this angiogenic growth factor on the retinal vasculature.

Young male pigs were injected with 600 microg hrIGF-1 into the vitreous cavity and were observed with serial examinations by ophthalmoscopy, fundus photography, and fluorescein angiography for varying periods up to 6 months. In a separate set of experiments, a dose-response relation was explored in animals injected with varying doses of IGF-1.

Histopathologic analysis included light and transmission electron microscopy and modified elastase digestion. Quantitative morphometric measurements were made of capillary basement membrane thickness and endothelial cell and pericyte densities of the retinal capillaries.

Early clinical features of IGF-1-injected eyes included marked arteriolar tortuosity, vitreitis, and retinal vessel and optic nerve head vascular fluorescein leakage. By 4 weeks, hyperfluorescent dots consistent with microaneurysms appeared and increased in number until 8 weeks postinjection. Clinical findings did not change appreciably after 8 weeks. Elastase digestion showed microaneurysms of the retinal capillaries and no ischemia or pericyte ghosts. Quantitative analysis of the digested specimens showed increased endothelial density by 1 month after injection (P < 0.05). Transmission electron microscopic cross-sections of capillaries showed significant basement membrane thickening by 3 months (P < 0.05). Lower doses of IGF-1 showed fewer clinical and histopathologic changes, and no significant changes were noted with a single 6 microg injection. Suspending hrIGF-1 in acidic buffer produced less intraocular inflammation than use of bovine serum albumin at neutral pH.

A single intravitreous injection of a large dose of hrIGF-1 produces a retinal microangiopathy that has a prolonged time of onset and remains stable from 2 to 6 months after injection. Some aspects of this angiopathy resemble diabetic retinopathy, suggesting growth factor effects in the morphologic vascular changes of diabetes.