HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Inhibition of pathologic retinal neovascularization by -defensins
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چکیده
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 5 1-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 fibrinmatrices. An up-regulation of 1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxiainduced 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 5 1-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. (Blood. 2005;106: 3831-3838)
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تاریخ انتشار 2005