title: Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes.
abstract: 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 Fas-FasL-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.
authors.affiliation: Retina Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA. JoussenA@aol.com
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Joussen
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Poulaki
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Wen-yi
authors.initials: WY
authors.lastname: Cai
authors.forename: Izumi
authors.initials: I
authors.lastname: Suzuma
authors.forename: John
authors.initials: J
authors.lastname: Pak
authors.forename: Shyr-Te
authors.initials: ST
authors.lastname: Ju
authors.forename: Susan L
authors.initials: SL
authors.lastname: Rook
authors.forename: Peter
authors.initials: P
authors.lastname: Esser
authors.forename: Constantin S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Bernd
authors.initials: B
authors.lastname: Kirchhof
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Adamis
authors.forename: Lloyd Paul
authors.initials: LP
authors.lastname: Aiello
mesh_terms: D000818:Animals; D017209:Apoptosis; D001813:Blood-Retinal Barrier; D002448:Cell Adhesion; D016923:Cell Death; D018920:Coculture Techniques; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology; D053222:Fas Ligand Protein; D007962:Leukocytes / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D018448:Models, Immunological; D009504:Neutrophils / Q000276:immunology; D051381:Rats; D012160:Retina / Q000166:cytology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D019014:fas Receptor