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American Journal of Pathology, Vol 145, 574-584, Copyright © 1994 by American Society for Investigative Pathology

REGULAR ARTICLES

Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model

JW Miller, AP Adamis, DT Shima, PA D'Amore, RS Moulton, MS O'Reilly, J Folkman, HF Dvorak, LF Brown and B Berse
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston 02114.

Ischemia often precedes neovascularization. In ocular neovascularization, such as occurs in diabetic retinopathy, a diffusible angiogenic factor has been postulated to be produced by ischemic retina and to lead to neovascularization of the retina, optic nerve, or iris. However, no angiogenic factor has been conclusively identified that satisfies this hypothesis. Vascular endothelial growth factor/vascular permeability factor, hereafter referred to as VEGF, is a likely candidate for an ocular angiogenic factor because it is a secreted mitogen, specific for endothelial cells, and is upregulated by hypoxia. We investigated the association of VEGF with the development of experimental iris neovascularization in the cynomolgus monkey. Following the production of retinal ischemia by laser occlusion of all branch retinal veins, VEGF was increased in the aqueous fluid, and the aqueous VEGF levels changed synchronously and proportionally with the severity of iris neovascularization. Northern analysis and in situ hybridization revealed that VEGF messenger RNA is upregulated in the ischemic retina. These observations support the hypothesis that ocular neovascularization is regulated by a diffusible factor and identify VEGF as a likely candidate for a retina-derived vascular permeability and angiogenesis factor in vivo.


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R. N. Frank, R. Amin, A. Kennedy, and T. C. Hohman
An Aldose Reductase Inhibitor and Aminoguanidine Prevent Vascular Endothelial Growth Factor Expression in Rats With Long-term Galactosemia
Arch Ophthalmol, August 1, 1997; 115(8): 1036 - 1047.
[Abstract] [PDF]

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 Br J OphthalmolHome page
R. O SCHLINGEMANN and V. W M VAN HINSBERGH
Role of vascular permeability factor/vascular endothelial growth factor in eye disease
Br J Ophthalmol, June 1, 1997; 81(6): 501 - 512.
[Full Text] [PDF]

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 Endocr. Rev.Home page
N. Ferrara and T. Davis-Smyth
The Biology of Vascular Endothelial Growth Factor
Endocr. Rev., February 1, 1997; 18(1): 4 - 25.
[Abstract] [Full Text]

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 Br J OphthalmolHome page
M. Kliffen, H. S Sharma, C. M Mooy, S. Kerkvliet, and P. T V M de Jong
Increased expression of angiogenic growth factors in age-related maculopathy
Br J Ophthalmol, February 1, 1997; 81(2): 154 - 162.
[Abstract] [Full Text] [PDF]

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 Arch OphthalmolHome page
C. K. Dorey, S. Aouididi, X. Reynaud, H. F. Dvorak, and L. F. Brown
Correlation of Vascular Permeability Factor/Vascular Endothelial Growth Factor With Extraretinal Neovascularization in the Rat
Arch Ophthalmol, October 1, 1996; 114(10): 1210 - 1217.
[Abstract] [PDF]

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 Arch OphthalmolHome page
E. A. Pierce, E. D. Foley, and L. E. H. Smith
Regulation of Vascular Endothelial Growth Factor by Oxygen in a Model of Retinopathy of Prematurity
Arch Ophthalmol, October 1, 1996; 114(10): 1219 - 1228.
[Abstract] [PDF]

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 Arch OphthalmolHome page
L. P. Aiello
Vascular Endothelial Growth Factor and the Eye: Past, Present, and Future
Arch Ophthalmol, October 1, 1996; 114(10): 1252 - 1254.
[Abstract] [PDF]

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 Arch OphthalmolHome page
M. J. Tolentino, J. W. Miller, E. S. Gragoudas, K. Chatzistefanou, N. Ferrara, and A. P. Adamis
Vascular Endothelial Growth Factor Is Sufficient to Produce Iris Neovascularization and Neovascular Glaucoma in a Nonhuman Primate
Arch Ophthalmol, August 1, 1996; 114(8): 964 - 970.
[Abstract] [PDF]

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 JAMAHome page
L. A. Levin
Ophthalmology
JAMA, June 19, 1996; 275(23): 1834 - 1836.
[Abstract] [PDF]

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 J. Biol. Chem.Home page
D. T. Shima, M. Kuroki, U. Deutsch, Y.-S. Ng, A. P. Adamis, and P. A. D'Amore
The Mouse Gene for Vascular Endothelial Growth Factor
J. Biol. Chem., February 16, 1996; 271(7): 3877 - 3883.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
K. D. O'Brien, T. O. McDonald, A. Chait, M. D. Allen, and C. E. Alpers
Neovascular Expression of E-Selectin, Intercellular Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Human Atherosclerosis and Their Relation to Intimal Leukocyte Content
Circulation, February 15, 1996; 93(4): 672 - 682.
[Abstract] [Full Text]

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 Arch OphthalmolHome page
A. P. Adamis, D. T. Shima, M. J. Tolentino, E. S. Gragoudas, N. Ferrara, J. Folkman, P. A. D'Amore, and J. W. Miller
Inhibition of Vascular Endothelial Growth Factor Prevents Retinal Ischemia--Associated Iris Neovascularization in a Nonhuman Primate
Arch Ophthalmol, January 1, 1996; 114(1): 66 - 71.
[Abstract] [PDF]

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 NEJMHome page
J. Folkman
Clinical Applications of Research on Angiogenesis
N. Engl. J. Med., December 28, 1995; 333(26): 1757 - 1763.
[Full Text] [PDF]

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 ScienceHome page
M. Friedlander, P. C. Brooks, R. W. Shaffer, C. M. Kincaid, J. A. Varner, and D. A. Cheresh
Definition of Two Angiogenic Pathways by Distinct alpha(v) Integrins
Science, December 1, 1995; 270(5241): 1500 - 1502.
[Abstract] [PDF]

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 Arch OphthalmolHome page
L. P. Aiello, J. M. Northrup, B. A. Keyt, H. Takagi, and M. A. Iwamoto
Hypoxic Regulation of Vascular Endothelial Growth Factor in Retinal Cells
Arch Ophthalmol, December 1, 1995; 113(12): 1538 - 1544.
[Abstract] [PDF]

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 J. Cell Sci.Home page
W. Roberts and G. Palade
Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor
J. Cell Sci., January 6, 1995; 108(6): 2369 - 2379.
[Abstract] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
A. Otani, B. M. Slike, M. I. Dorrell, J. Hood, K. Kinder, K. L. Ewalt, D. Cheresh, P. Schimmel, and M. Friedlander
A fragment of human TrpRS as a potent antagonist of ocular angiogenesis
PNAS, January 8, 2002; 99(1): 178 - 183.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
V. Stellmach, S. E. Crawford, W. Zhou, and N. Bouck
Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor
PNAS, February 27, 2001; 98(5): 2593 - 2597.
[Abstract] [Full Text] [PDF]


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