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Science 9 July 1999:
Vol. 285. no. 5425, pp. 245 - 248
DOI: 10.1126/science.285.5425.245
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Reports

Pigment Epithelium-Derived Factor: A Potent Inhibitor of Angiogenesis

D. W. Dawson, 13 O. V. Volpert, 13 P. Gillis, 13 S. E. Crawford, 23 H.-J. Xu, 4 W. Benedict, 5 N. P. Bouck 13*

In the absence of disease, the vasculature of the mammalian eye is quiescent, in part because of the action of angiogenic inhibitors that prevent vessels from invading the cornea and vitreous. Here, an inhibitor responsible for the avascularity of these ocular compartments is identified as pigment epithelium-derived factor (PEDF), a protein previously shown to have neurotrophic activity. The amount of inhibitory PEDF produced by retinal cells was positively correlated with oxygen concentrations, suggesting that its loss plays a permissive role in ischemia-driven retinal neovascularization. These results suggest that PEDF may be of therapeutic use, especially in retinopathies where pathological neovascularization compromises vision and leads to blindness.

1 Department of Microbiology-Immunology,
2 Department of Pathology,
3 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL 60611, USA.
4 Department of Molecular Oncology,
5 Department of Genitourinary Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
*   To whom correspondence should be addressed. E-mail: n-bouck{at}nwu.edu

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Br J Ophthalmol 89, 864-870
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Two Functional Epitopes of Pigment Epithelial-Derived Factor Block Angiogenesis and Induce Differentiation in Prostate Cancer.
S. Filleur, K. Volz, T. Nelius, Y. Mirochnik, H. Huang, T. A. Zaichuk, M. S. Aymerich, S. P. Becerra, R. Yap, D. Veliceasa, et al. (2005)
Cancer Res. 65, 5144-5152
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Kringle 5 of Human Plasminogen Induces Apoptosis of Endothelial and Tumor Cells through Surface-Expressed Glucose-Regulated Protein 78.
D. J. Davidson, C. Haskell, S. Majest, A. Kherzai, D. A. Egan, K. A. Walter, A. Schneider, E. F. Gubbins, L. Solomon, Z. Chen, et al. (2005)
Cancer Res. 65, 4663-4672
   Abstract »    Full Text »    PDF »
Physiological role of collagen XVIII and endostatin.
A. G. Marneros and B. R. Olsen (2005)
FASEB J 19, 716-728
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Endogenous inhibitors of angiogenesis in malignant gliomas: Nature's antiangiogenic therapy.
T. A. Rege, C. Y. Fears, and C. L. Gladson (2005)
Neuro-oncol 7, 106-121
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Strain-Dependent Differences in Oxygen-Induced Retinopathy in the Inbred Rat.
P. van Wijngaarden, D. J. Coster, H. M. Brereton, I. L. Gibbins, and K. A. Williams (2005)
Invest. Ophthalmol. Vis. Sci. 46, 1445-1452
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Altered Gene Expression of Angiogenic Factors Induced by Calcium-Mediated Dissociation of Retinal Pigment Epithelial Cells.
X.-F. Wang, J. Z. Cui, S. S. Prasad, and J. A. Matsubara (2005)
Invest. Ophthalmol. Vis. Sci. 46, 1508-1515
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The Role of the Anti-Angiogenic Factor Endostatin in Intrauterine Growth Restriction.
A. Malamitsi-Puchner, T. Boutsikou, E. Economou, E. Makrakis, Z. Iliodromiti, E. Kouskouni, and D. Hassiakos (2005)
Reproductive Sciences 12, 195-197
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Pigment epithelium-derived factor inhibits fibroblast-growth-factor-2-induced capillary morphogenesis of endothelial cells through Fyn.
S. Kanda, Y. Mochizuki, T. Nakamura, Y. Miyata, T. Matsuyama, and H. Kanetake (2005)
J. Cell Sci. 118, 961-970
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Inhibition of Tumor Necrosis Factor-{alpha} Improves Physiological Angiogenesis and Reduces Pathological Neovascularization in Ischemic Retinopathy.
T. A. Gardiner, D. S. Gibson, T. E. de Gooyer, V. F. de la Cruz, D. M. McDonald, and A. W. Stitt (2005)
Am. J. Pathol. 166, 637-644
   Abstract »    Full Text »    PDF »
Extracellular phosphorylation converts pigment epithelium-derived factor from a neurotrophic to an antiangiogenic factor.
G. Maik-Rachline, S. Shaltiel, and R. Seger (2005)
Blood 105, 670-678
   Abstract »    Full Text »    PDF »
Decreased Expression of Pigment Epithelium-Derived Factor Is Involved in the Pathogenesis of Diabetic Nephropathy.
J. J. Wang, S. X. Zhang, K. Lu, Y. Chen, R. Mott, S. Sato, and J.-x. Ma (2005)
Diabetes 54, 243-250
   Abstract »    Full Text »    PDF »
Crystal Structure of Human Maspin, a Serpin with Antitumor Properties: REACTIVE CENTER LOOP OF MASPIN IS EXPOSED BUT CONSTRAINED.
M. Al-Ayyoubi, P. G. W. Gettins, and K. Volz (2004)
J. Biol. Chem. 279, 55540-55544
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Stimulation of Neovascularization by the Anti-angiogenic Factor PEDF.
R. S. Apte, R. A. Barreiro, E. Duh, O. Volpert, and T. A. Ferguson (2004)
Invest. Ophthalmol. Vis. Sci. 45, 4491-4497
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Diabetic Retinopathy.
D. S. Fong, L. P. Aiello, F. L. Ferris III, and R. Klein (2004)
Diabetes Care 27, 2540-2553
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Effect of inhibition of multiple steps of angiogenesis in syngeneic murine pleural mesothelioma.
R. E. Merritt, R. E. Yamada, N. Wasif, R. G. Crystal, and R. J. Korst (2004)
Ann. Thorac. Surg. 78, 1042-1051
   Abstract »    Full Text »    PDF »
Autocrine effects of IGF-I-induced VEGF and IGFBP-3 secretion in retinal pigment epithelial cell line ARPE-19.
M. G. Slomiany and S. A. Rosenzweig (2004)
Am J Physiol Cell Physiol 287, C746-C753
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Inhibition of Xenografted Human Melanoma Growth and Prevention of Metastasis Development by Dual Antiangiogenic/Antitumor Activities of Pigment Epithelium-Derived Factor.
M. Garcia, N. I. Fernandez-Garcia, V. Rivas, M. Carretero, M. J. Escamez, A. Gonzalez-Martin, E. E. Medrano, O. Volpert, J. L. Jorcano, B. Jimenez, et al. (2004)
Cancer Res. 64, 5632-5642
   Abstract »    Full Text »    PDF »
Decreased Pigment Epithelium-Derived Factor Is Associated with Metastatic Phenotype in Human and Rat Prostate Tumors.
S. Halin, P. Wikstrom, S. H. Rudolfsson, P. Stattin, J. A. Doll, S. E. Crawford, and A. Bergh (2004)
Cancer Res. 64, 5664-5671
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In Vitro Antiangiogenic Activity in Ex Vivo Expanded Human Limbocorneal Epithelial Cells Cultivated on Human Amniotic Membrane.
D. H.-K. Ma, J.-Y. Yao, L.-K. Yeh, S.-T. Liang, L.-C. See, H.-T. Chen, K.-Y. Lin, C.-C. Liang, K.-K. Lin, and J.-K. Chen (2004)
Invest. Ophthalmol. Vis. Sci. 45, 2586-2595
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IGF-1-Induced VEGF and IGFBP-3 Secretion Correlates with Increased HIF-1{alpha} Expression and Activity in Retinal Pigment Epithelial Cell Line D407.
M. G. Slomiany and S. A. Rosenzweig (2004)
Invest. Ophthalmol. Vis. Sci. 45, 2838-2847
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Pigment Epithelium-derived Factor in Idiopathic Pulmonary Fibrosis: A Role in Aberrant Angiogenesis.
G. P. Cosgrove, K. K. Brown, W. P. Schiemann, A. E. Serls, J. E. Parr, M. W. Geraci, M. I. Schwarz, C. D. Cool, and G. S. Worthen (2004)
Am. J. Respir. Crit. Care Med. 170, 242-251
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Nuclear Factor of Activated T Cells Balances Angiogenesis Activation and Inhibition.
T. A. Zaichuk, E. H. Shroff, R. Emmanuel, S. Filleur, T. Nelius, and O. V. Volpert (2004)
J. Exp. Med. 199, 1513-1522
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Suppression of Corneal Neovascularization by PEDF Release from Human Amniotic Membranes.
C. Shao, J. Sima, S. X. Zhang, J. Jin, P. Reinach, Z. Wang, and J.-x. Ma (2004)
Invest. Ophthalmol. Vis. Sci. 45, 1758-1762
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Expression of pigment epithelium derived factor and vascular endothelial growth factor in choroidal neovascular membranes and polypoidal choroidal vasculopathy.
M Matsuoka, N Ogata, T Otsuji, T Nishimura, K Takahashi, and M Matsumura (2004)
Br J Ophthalmol 88, 809-815
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