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M. Economopoulou, K. Bdeir, D.B. Cines, F. Fogt, Y. Bdeir, J. Lubkowski, H.–P. Hammes, T. Chavakis; Inhibition of Pathologic Retinal Neovascularization by –Defensins . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1438.
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© ARVO (1962-2015); The Authors (2016-present)
A hallmark of proliferative retinopathies is excessive neovascularization, which is controlled by both the hypoxia–induced vascular endothelial growth factor (VEGF) and integrin–mediated adhesive interactions of endothelial cells with extracellular matrix components such as fibronectin (FN). Recently, we demonstrated that α–defensins interfere with α5ß1–FN interactions and dependent endothelial cell functions. Here, α–defensins were studied in hypoxia–induced proliferative retinopathy.
The effect of α–defensins on adhesion, migration, proliferation paracellular permeability and sprout formation of bovine retinal endothelial cells (BREC) was studied in vitro. In vivo, the model of retinopathy of prematurity (ROP) was engaged. In addition, immunofluorescence was performed for the detection of α–defensins in diabetic and non–diabetic human retinas.
In vitro, α–defensins specifically inhibited α5ß1–integrin–dependent adhesion and migration of BREC to FN but not to other matrix proteins. Moreover, α–defensins 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 ß1–integrin and FN was observed in the retinal vessels during hypoxia–induced neovascularization in the ROP model. In this model, systemic and local (subconjuctival) administration of α–defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of α5ß1–blocking antibody. Furthermore, α–defensins significantly decreased vascular permeability in the retina of ROP mice. Finally, 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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