Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is a potent ischemia-upregulated angiogenic protein that has been implicated in diabetic retinopathy. Intravitreal VEGF injections have not previously been shown to produce preretinal neovascularization. The purpose of this study was to further characterize the angiopathic changes that occur after intravitreal injections in a nonhuman primate and determine if preretinal neovascularization develops.


METHODS
Experimental animal study.


METHODS
Vascular endothelial growth factor 165 was injected into the eyes of normal cynomolgus monkeys at regular intervals. As a control, normal eyes were injected with phosphate buffered saline. Color photography and fluorescein angiography were performed at regular intervals. The retinas were incubated for adenosine diphosphatase (ADPase) activity to visualize retinal vessels. The retinas were flat-embedded and areas of potential preretinal neovascularization were identified en bloc and serially sectioned.


RESULTS
Areas of capillary nonperfusion and vessel dilation and tortuousity were seen by angiography. In serial sections, the nonperfused areas were found to be associated with endothelial cell hyperplasia in vessel lumens. Preretinal neovascularization originating only from superficial veins and venules was observed throughout peripheral retina, but was not seen in the posterior pole. Lacunae-like veins were subdivided by the process of intussusception and endothelial cell bridging. Arterioles demonstrated endothelial cell hyperplasia and microaneurysms.


CONCLUSIONS
Intraocular injections of VEGF were sufficient to produce preretinal neovascularization in the nonhuman primate. Most vasculopathic structures were associated with endothelial cell hyperplasia. These results demonstrate that VEGF alone can produce many features of both nonproliferative and proliferative diabetic retinopathy including the previously undescribed development of preretinal neovascularization. This well-characterized VEGF-induced primate model of retinal neovascularization may be useful as a means of testing new treatments for retinal neovascularization.
Tolentino
Michael J
MJ
F. M. Kirby Center for Molecular Ophthalmology and Retina Service, Scheie Eye Institute University of Pennsylvania, Philadelphia, USA.
McLeod
D Scott
DS
Taomoto
Makoto
M
Otsuji
Tsuyoshi
T
Adamis
Anthony P
AP
Lutty
Gerard A
GA
D000818:Animals; D001081:Apyrase / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000473:pathology*; D016228:Endothelial Growth Factors / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000473:pathology; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D007267:Injections; D008222:Lymphokines / Q000633:toxicity*; D008252:Macaca fascicularis; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000473:pathology*; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014822:Vitreous Body
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001081:Apyrase