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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3831-3838.
Prepublished online as a Blood First Edition Paper on August 25, 2005; DOI 10.1182/blood-2005-03-0889.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Inhibition of pathologic retinal neovascularization by  -defensins
Matina Economopoulou,
Khalil Bdeir,
Douglas B. Cines,
Franz Fogt,
Yasmina Bdeir,
Jacek Lubkowski,
Wuyuan Lu,
Klaus T. Preissner,
Hans-Peter Hammes, and
Triantafyllos Chavakis
From the Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Internal Medicine V, University Clinic Mannheim, Germany; Department of Ophthalmology, Justus-Liebig-University, Giessen, Germany; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA; Macromolecular Assembly Structure and Cell Signaling Section, National Cancer Institute, Frederick, MD; Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD; and Institute for Biochemistry, Justus-Liebig-University, Giessen, Germany.
Proliferative retinopathies, such as those complicating prematurity and diabetes, are major causes of blindness. A prominent feature of these retinopathies is excessive neovascularization, which is orchestrated by the hypoxia-induced vascular endothelial growth factor (VEGF) stimulating endothelial cells and the integrin-mediated adhesive interactions of endothelial cells with extracellular matrix components such as fibronectin (FN). Recently, we demonstrated that  -defensins interfere with 5 1–FN interactions and dependent endothelial cell functions. Here, -defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, -defensins specifically inhibited 51-integrin–dependent migration of bovine retinal endothelial cells (BRECs) to FN, attenuated the VEGF-stimulated increase in endothelial permeability, and blocked BREC proliferation and capillary sprout formation in 3-dimensional fibrin-matrices. An up-regulation of 1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxia-induced retinal angiogenesis. Systemic and local administration of -defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of 51-blocking antibody. -Defensins were detected in human diabetic retinas associated with normal retinal vessels but were absent from proliferative lesions. Together, these data show that -defensins inhibit pathologic retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies.
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