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Article
January 1996

Inhibition of Vascular Endothelial Growth Factor Prevents Retinal Ischemia—Associated Iris Neovascularization in a Nonhuman Primate

Author Affiliations

From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary (Drs Adamis, Tolentino, Gragoudas, and Miller), Laboratory for Surgical Research, Department of Surgery, Children's Hospital (Drs Adamis, Shima, Tolentino, Folkman, and D'Amore), Program in Cell and Developmental Biology (Dr Shima), and Department of Pathology (Dr D'Amore), Harvard Medical School, Boston, Mass; and the Department of Cardiovascular Research, Genentech Inc, South San Francisco, Calif (Dr Ferrara).

Arch Ophthalmol. 1996;114(1):66-71. doi:10.1001/archopht.1996.01100130062010
Abstract

Objective:  To determine if the angiogenic peptide vascular endothelial growth factor (VEGF) is required for retinal ischemia—associated iris neovascularization in a nonhuman primate.

Methods:  Laser retinal vein occlusion was used to produce retinal ischemia in 16 eyes of eight animals (Macaca fascicularis). Eyes were randomized to treatment every other day with intravitreal injections of either a neutralizing anti-VEGF monoclonal antibody or a control monoclonal antibody of the same isotype. Serial iris fluorescein angiograms were assessed using a standardized grading system and masked readers. Retinal VEGF and placental growth factor expression were assessed by Northern blotting. The specificity of the antibodies was determined in capillary endothelial cell proliferation assays prior to intravitreal injection.

Results:  Zero of eight eyes receiving the neutralizing anti-VEGF antibodies developed iris neovascularization. Five of eight control antibody-treated eyes developed iris neovascularization. The difference was statistically significant (P=.03). Intravitreal antibody injection did not impair the ability of the ischemic retina to increase VEGF messenger RNA expression. The anti-VEGF antibodies specifically inhibited VEGF-driven capillary endothelial cell proliferation in vitro.

Conclusion:  These data demonstrate that VEGF is required for iris neovascularization in an adult nonhuman primate eye. The inhibition of VEGF is a new potential therapeutic strategy for the treatment of ocular neovascularization.

References
1.
Michaelson IC.  The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases . Trans Ophthalmol Soc U K . 1948;68:137-180.
2.
Ashton N.  Retinal vascularization in health and disease . Am J Ophthalmol . 1957;44:7-24.
3.
Wise GN.  Retinal neovascularization . Trans Am Ophthalmol Soc . 1956;54:729-826.
4.
D'Amore PA.  Mechanisms of retinal and choroidal neovascularization . Invest Ophthalmol Vis Sci . 1994;35:3974-3978.
5.
Shweiki D, Itin A, Softer D, Keshet E.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis . Nature . 1992;359:843-845.Article
6.
Shima DT, Adamis AP, Ferrara N, Allende R, Yeo K, D'Amore PA.  Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor as the mitogen . Mol Med . 1995;2:64-75.
7.
Plate KH, Breier G, Weich HA, Risau W.  Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo . Nature . 1992;359:845-848.Article
8.
Miller J, Adamis AP, Shima DT, et al.  Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model . Am J Pathol . 1994;145:574-584.
9.
Adamis AP, Miller J, Bernal M, et al.  Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy . Am J Ophthalmol . 1994;118:445-450.
10.
Malecaze F, Clamens S, Simorre-Pinatel V, et al.  Detection of vascular endothelial growth factor messanger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy . Arch Ophthalmol . 1994;112:1476-1482.Article
11.
Aiello LP, Avery RL, Arrigg PG, et al.  Vascular endothelial growth factor in ocular fluid of patients wth diabetic retinopathy and other retinal disorders . N Engl J Med . 1994;331:1480-1487.Article
12.
Kim KJ, Li B, Winer J, et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo . Nature . 1993;362:841-844.Article
13.
Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A.  Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant . Nature . 1994;367:576-579.Article
14.
Virdi PS, Hayreh SS.  Ocular neovascularization with retinal vascular occlusion, I: association with experimental vein occlusion . Arch Ophthalmol . 1982;100:331-341.Article
15.
Jiang LQ, Jorquera M, Streilein JW.  Subretinal space and vitreous cavity as immunologically privileged sites for retinal allografts . Invest Ophthalmol Vis Sci . 1993;34:3347-3354.
16.
Nork TM, Tso MO, Duvall J, Hayreh SS.  Cellular mechanisms of iris neovascularization secondary to retinal vein occlusion . Arch Ophthalmol . 1989;107:581-586.Article
17.
Landis JR, Koch GG.  The measurement of observer agreement for categorical data . Biometrics . 1977;33:159-174.Article
18.
Kim KJ, Li B, Houck K, Winer J, Ferrara N.  The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies . Growth Factors . 1992;7:53-64.Article
19.
Maglione D, Guerriero V, Vigliette G, Delli-Bovi P, Persico MG.  Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor . Proc Natl Acad Sci U S A . 1991;88:9267-9271.Article
20.
Rothman KJ.  Matching . In: Modern Epidemiology . Boston, Mass: Little Brown & Co Inc; 1986:275-279.
21.
Frank RN.  Vascular endothelial growth factor: its role in retinal vascular proliferation . N Engl J Med . 1994;331:1519-1520.Article
22.
Goto F, Goto K, Weindel K, Folkman J.  Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels . Lab Invest . 1993;69:508-517.
23.
Pepper MS, Ferrara N, Orci L, Montesano R.  Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro . Biochem Biophys Res Commun . 1992;189:824-831.Article
24.
Sivalingam A, Kenney GC, Brown WE, Benson L, Donoso L.  Basic fibroblast growth factor levels in the vitreous of patients with proliferative diabetic retinopathy . Arch Ophthalmol . 1990;108:869-872.Article
25.
Miller JW, Stinson WG, Folkman J.  Regression of experimental iris neovascularization with systemic alpha-interferon . Ophthalmology . 1993;100:9-14.Article
26.
Miller JW, Stinson WG, Gregory WA, El-Koumy HA, Puliafito CA.  Phthalocyanine photodynamic therapy of experimental iris neovascularization . Ophthalmology . 1991;98:1711-1719.Article
27.
Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LEH.  Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization . Proc Natl Acad Sci U S A . 1995;92:905-909.Article
28.
Stone J, Itan A, Alon T, Gnessin H, Chan-Ling T, Keshet E.  Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia . J Neurosci . 1995;15:4738-4747.
29.
Simorre-Pinatel V, Guerrin M, Chollet P, et al.  Vasculotropin-VEGF stimulates retinal capillary endothelial cells through an autocrine pathway . Invest Ophthalmol Vis Sci . 1994;35:3393-3400.
30.
Thieme H, Aiello LP, Takagi H, Ferrara N, King GL.  Comparitive analysis of vascular endothelial growth factor receptors on retinal and aortic vascular endothelial cells . Diabetes . 1995;44:98-103.Article
31.
Plouet J, Schilling J, Gospodarowicz D.  Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT20 cells . EMBO J . 1989;8:3801-3806.
32.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N.  Vascular endothelial growth factor is a secreted angiogenic mitogen . Science . 1989;246:1306-1309.Article
33.
Connolly DT, Hewelman DM, Nelson R, et al.  Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis . J Clin Invest . 1989;84:1478-1489.
34.
Takeshita S, Zheng LP, Brogi E, et al.  Therapeutic angiogenesis: a single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model . J Clin Invest . 1994;93:662-670.Article
35.
Tolentino MJ, Miller JW, Gragoudas ES, et al.  Vascular endothelial growth factor is sufficient to produce ocular neovascularization in a non-human primate . Invest Ophthalmol Vis Sci . 1995;36( (suppl) ):1869.
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