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: Matina Economopoulou, Khalil Bdeir, Douglas B Cines, Franz Fogt, Yasmina Bdeir, Jacek Lubkowski, Wuyuan Lu, Klaus T Preissner, Hans-Peter Hammes, Triantafyllos Chavakis
• Journal: Blood (Blood) Vol. 106 Issue 12 Pg. 3831-8 (Dec 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 16123222 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• alpha-Defensins

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Cell Adhesion (drug effects, physiology)
• Cell Movement (drug effects, physiology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism)
• Humans
• Hypoxia (physiopathology)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Retina (metabolism, pathology, physiopathology)
• Retinal Diseases (metabolism, physiopathology)
• Retinal Neovascularization (metabolism, physiopathology)
• Retinal Vessels (metabolism)
• alpha-Defensins (metabolism, pharmacology)