Vascular endothelial growth factor induces retinal capillary dilatation and breakdown of blood-retinal barrier in primates

Purpose. Vascular endothelial growth factor (VEGF) plays a role in the development of retinal neovascularization(NV), but it is not known if increased levels of VEGF alone are sufficient to produce retinal NV. Also, while VEGF is a potent inducer of vascular permeability in some tissues, it is not known if it increases the permeability of retinal vessels (RVs) which differ in barrier characteristics from vessels in most other tissues. This study was designed to determine if sustained release of VEGF in the vitreous cavity of primates causes retinal NV and/or breakdown of blood-retinal barrier (BRB). Methods. Ethylene-vinyl acetate pellets containing 100 μg of human recombinant VEGF(165) or vehicle (controls) were each implanted into the vitreous cavity of 3 eyes of cynomolgus monkeys. Eyes were followed by indirect ophthalmoscopy, fundus photography, and fluorescein angiography(FA). Monkeys were sacrificed 3, 4, or 5 weeks after pellet implantation and eyes were enucleated and examined with light and electron microscopic albumin immunocytochemistry. Results. One week after implantation, eyes with a VEGF pellet showed dilatation and tortuosity of iris vessels and retinal vessels adjacent to pellets. Over the next two weeks dilatation of iris vessels decreased, while dilatation of retinal vessels increased and became generalized throughout the retina; thereafter, RVs became less dilated. Two weeks after implantation, FA showed extensive leakage through dilated retinal vessels. Immunocytochemical staining showed serum albumin extending around dilated vessels of the inner capillary plexus, but not around those of the outer capillary plexus which were not dilated and appeared normal; there was also albumin in RPE and around photoreceptors. Ultrastructure of RVs showed some areas consistent with endothelial sprouts suggesting early NV, but widespread NV was not seen. Control eyes were normal. Conclusion. Sustained release of VEGF in the vitreous cavity of primates causes dilation of retinal and iris vessels and breakdown of the inner and outer BRBs.