INTRAVITREAL SUSTAINED-RELEASE OF VEGF CAUSES RETINAL NEOVASCULARIZATION IN RABBITS AND BREAKDOWN OF THE BLOOD-RETINAL BARRIER IN RABBITS AND PRIMATES

Vascular endothelial growth factor (VEGF) has been identified as a pos sible mediator of retinal neooascularization (NV), but it is not certa in if VEGF alone is sufficient to cause retinal NV. We sought to inves tigate this issue by implanting ethylene-vinyl acetate copolymer pelle ts that slowly release VEGF into the vitreous cavity of rabbits and pr imates. Eyes were examined by indirect ophthalmoscopy, fundus photogra phy, and fluorescein angiography and then animals were killed at vario us time points and immunocytochemical and ultrastructural evaluations were carried out. Seven days after implantation of a pellet containing 30 mu g of human recombinant VEGP into the vitreous cavity of rabbits , retinal blood vessels became dilated and tortuous, and between days 14 and 21, retinal NV was noted in all eyes. Fluorescein angiography s howed profuse leakage of dye from the anomalous vessels. Immunohistoch emical staining for proliferating cell nuclear antigen (PCNA) showed p ositively staining nuclei in many of the endothelial cells of new bloo d vessels on the surface of the retina. Six eyes implanted with contro l pellets containing vehicle and two eyes implanted with pellets conta ining 30 mu g of human serum albumin alone showed no retinal Vascular abnormalities. Implantation of pellets containing 100 mu g of VEGF int o the vitreous cavity of primates resulted in iris NV and retinal vasc ular dilation and tortuosity very much like that seen in humans with i schemic retinopathies. Immunohistochemical staining for serum albumin showed widespread severe breakdown of the blood-retinal barrier (BRB). Histology showed dilated thin-walled retinal vessels, but unequivocal retinal NV could not be identified and staining for PCNA was negative . These findings indicate that sustained intravitreal release of VEGF causes widespread retinal vascular dilation and breakdown of the BRB. Retinal NV seems to require persistent high levels of VEGF at the reti nal surface and can be achieved in rabbits providing a potentially use ful model of retinal NV, but is difficult to achieve in primates. The extensive VEGF-induced disruption of the blood-retinal barrier suggest s that VEGF antagonists may provide a new therapy for patients with is chemic retinopathies and macular edema. (C) 1997 Academic Press Limite d.