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Michael J. Tolentino, MD; Joan W. Miller, MD; Evangelos S. Gragoudas, MD; Klio Chatzistefanou, MD; Napoleone Ferrara, MD; Anthony P. Adamis, MD

Arch Ophthalmol. 1996;114(8):964-970.

Abstract
Objective
To determine whether the angiogenic peptide vascular endothelial growth factor (VEGF) is sufficient to produce iris neovascularization in a nonhuman primate (Macaca fascicularis).

Methods
Eight eyes of 4 animals were studied. The 165amino acid isoform of human recombinant VEGF (VEGF₁₆₅) was injected into the vitreous of 5 cynomolgus monkey eyes (doses ranging from 0.25-2.5 µg per injection). Equal amounts of inactivated human recombinant VEGF (2 eyes) or vehicle (1 eye) were injected into contralateral control eyes. Eyes were assessed by slitlamp biomicroscopy, tonometry, iris color photography, fluorescein angiography, histopathologic examination, and immunostaining with antibodies against proliferating cell nuclear antigen.

Results
All 5 bioactive VEGF-injected eyes developed neovascularization with dilated and tortuous iris vessels that leaked fluorescein. None of the 3 control eyes exhibited any iris vascular changes. Inflammation was absent in both treatment groups. A dose response to VEGF was observed in the single animal that received 2.5 µg and 0.25 µg in the right and left eyes, respectively. Iris vessel endothelial cells were positive for proliferating cell nuclear antigen in the bioactive VEGF-injected eyes only. Injections of 1.25 µg of VEGF every 3 days during a 30-day period produced advanced iris neovascularization, ectropion uvea, and neovascular glaucoma.

Conclusions
Intravitreal injections of recombinant human VEGF₁₆₅ in amounts comparable with those 165 sured in eyes with active neovascularization are sufficient to produce noninflammatory iris neovascularization in a nonhuman primate. Prolonged exposure to VEGF₁₆₅ can produce ectropion uveae and neovascular glaucoma.

Author Affiliations
From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston (Drs Tolentino, Miller, Gragoudas, Chatzistefanou, and Adamis); Laboratory for Surgical Research, Department of Surgery, Children's Hospital, Boston (Drs Tolentino, Chatzistefanou, and Adamis); and Genentech Inc, South San Francisco, Calif (Dr Ferrara).

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