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Suppression of Fas‐FasL‐induced endothelial cell apoptosis prevents diabetic blood‐retinal barrier breakdown in a model of streptozotocin‐induced diabetes
Author(s) -
Joussen Antonia M.,
Poulaki Vassiliki,
Mitsiades Nicholas,
Cai Wenyi,
Suzuma Izumi,
Pak John,
Ju ShyrTe,
Rook Susan L.,
Esser Peter,
Mitsiades Constantin,
Kirchhof Bernd,
Adamis Anthony P.,
Paul Aiello Lloyd
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0157fje
Subject(s) - fas ligand , retinal , blood–retinal barrier , diabetic retinopathy , apoptosis , vascular permeability , streptozotocin , endothelial stem cell , diabetes mellitus , medicine , retina , endocrinology , immunology , biology , programmed cell death , in vitro , ophthalmology , biochemistry , neuroscience
Diabetic macular edema, resulting from increased microvascular permeability, is the most prevalent cause of vision loss in diabetes. The mechanisms underlying this complication remain poorly understood. In the current study, diabetic vascular permeability (blood‐retinal barrier breakdown) is demonstrated to result from a leukocyte‐mediated Fas‐FasL‐dependent apoptosis of the retinal vasculature. Following the onset of streptozotocin‐induced diabetes, FasL expression was increased in rat neutrophils ( P <0.005) and was accompanied by a simultaneous increase in Fas expression in the retinal vasculature. Static adhesion assays demonstrated that neutrophils from diabetic, but not control, rats induced endothelial cell apoptosis in vitro ( P <0.005). The latter was inhibited via an antibody‐based FasL blockade ( P <0.005). In vivo , the inhibition of FasL potently reduced retinal vascular endothelial cell injury, apoptosis, and blood‐retinal barrier breakdown ( P <0.0001) but did not diminish leukocyte adhesion to the diabetic retinal vasculature. Taken together, these data are the first to identify leukocyte‐mediated FasFasL‐dependent retinal endothelial cell apoptosis as a major cause of blood‐retinal barrier breakdown in early diabetes. These data imply that the targeting of the Fas‐FasL pathway may prove beneficial in the treatment of diabetic retinopathy.