Inhibition of pathologic retinal neovascularization by α-defensins

M Economopoulou, K Bdeir, DB Cines, F Fogt, Y Bdeir… - Blood, 2005 - ashpublications.org
M Economopoulou, K Bdeir, DB Cines, F Fogt, Y Bdeir, J Lubkowski, W Lu, KT Preissner
Blood, 2005ashpublications.org
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 α-defensins interfere with α5β1–FN interactions and …
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 α-defensins interfere with α5β1–FN interactions and dependent endothelial cell functions. Here, α-defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, α-defensins specifically inhibited α5β1-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 β1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxia-induced retinal angiogenesis. Systemic and local administration of α-defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of α5β1-blocking antibody. α-Defensins were detected in human diabetic retinas associated with normal retinal vessels but were absent from proliferative lesions. Together, these data show that α-defensins inhibit pathologic retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies.
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