title: Inhibition of pathologic retinal neovascularization by alpha-defensins.
abstract: 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 alpha-defensins interfere with alpha5beta1-FN interactions and dependent endothelial cell functions. Here, alpha-defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, alpha-defensins specifically inhibited alpha5beta1-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 beta1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxia-induced retinal angiogenesis. Systemic and local administration of alpha-defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of alpha5beta1-blocking antibody. alpha-Defensins were detected in human diabetic retinas associated with normal retinal vessels but were absent from proliferative lesions. Together, these data show that alpha-defensins inhibit pathologic retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Rm 4B17, 10 Center Dr, Bethesda, MD 20892, USA.
authors.forename: Matina
authors.initials: M
authors.lastname: Economopoulou
authors.forename: Khalil
authors.initials: K
authors.lastname: Bdeir
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Franz
authors.initials: F
authors.lastname: Fogt
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Bdeir
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubkowski
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D012160:Retina / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D012164:Retinal Diseases / Q000378:metabolism* / Q000503:physiopathology; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000503:physiopathology; D012171:Retinal Vessels / Q000378:metabolism*; D023084:alpha-Defensins / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D023084:alpha-Defensins