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.

Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

“…ICAM-1 on vascular endothelial cells is the key factor for leukocyte adhesion to the endothelium and for leukocyte migration into the tissue, 46 which causes endothelial cell injury followed by increased retinal vascular permeability, retinal edema, and loss of visual acuity. 6,7,9 It has been reported that ICAM-1 expression is up-regulated in diabetic retina, and is the main cause of leukocyte-endothelial cell interaction. [1][2][3] Therefore, the ability of statins to inhibit ICAM-1 expression indicates that statins can attenuate leukocyte-endothelial cell interactions and the subsequent endothelial damage and tissue injury.…”

“…In diabetic retinopathy, the expression of intercellular adhesion molecule-1 (ICAM-1) on the vascular endothelial cells is up-regulated, [1][2][3] which leads to leukocyte adhesion to vascular endothelium and to accumulation of leukocytes within the retina. 1,4,5 Leukocytes that are adherent to vascular endothelium have been shown to cause capillary occlusion, 1,4,5 endothelial cell apoptosis, 6,7 and, finally, blood-retinal barrier breakdown (BRB). 1,[7][8][9] These damages result in clinical symptoms of diabetic retinopathy, such as areas of nonperfusion, retinal hemorrhage because of vascular vulnerability, and retinal edema each of which can cause serious loss of visual acuity.…”

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

“…However, the literature supports the concept that macrophages and inflammatory cells play a major role in the development of vascular alterations in diabetes. 68,69 One possible mechanism whereby ACE2 overexpression attenuates the diabetes-associated increase of macrophage/ microglial cells ( Figure 5) is attributable to the ability of Ang(1-7) to antagonize AGTR1s (which are expressed on microglia). AGTR1 blockade with valsartan effectively decreased microglial density in a rodent model of DR. 70 Consistent with our findings, McVicar et al 65 found a significant increase of F4/80 þ microglia in the retina when compared with nondiabetic controls, after 3 and 6 months of diabetes in mice.…”

Diabetic Retinopathy

“…In addition, elevated levels of complement and reduced levels of complement inhibitors (67) and acute-phase proteins (68) are likely key events in the phagocytic clearance of necrotic and apoptotic neurons (12). Recent evidence strongly suggests that inflammation involving vessels and neural tissue occurs early in experimental (11,64,65,67,69) and human (70) retinopathy, involving humoral and cellular components of innate immunity.…”