Inhibition of pathologic retinal neovascularization by alpha-defensins

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Matina Economopoulou - , National Cancer Institute (NCI) (First author)
  • Khalil Bdeir - , National Cancer Institute (NCI), University of Pennsylvania (Author)
  • Douglas B Cines - , National Cancer Institute (NCI) (Author)
  • Franz Fogt - (Author)
  • Yasmina Bdeir - (Author)
  • Jacek Lubkowski - (Author)
  • Wuyuan Lu - (Author)
  • Klaus T. Preissner - , Justus Liebig University Giessen (Author)
  • Hans-Peter Hammes - (Author)
  • Triantafyllos Chavakis - , Justus Liebig University Giessen (Last author)

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.

Details

Original languageEnglish
Pages (from-to)3831-3838
JournalBlood
Publication statusPublished - 2 Dec 2005
Peer-reviewedYes
Externally publishedYes

External IDs

PubMed 16123222
Scopus 28444480677

Keywords