Abstract
PurposeTo characterize the relationship between endothelin-1 and fibrosis in epiretinal membranes in proliferative diabetic retinopathy and explore the role of endothelial-mesenchymal transition in these membranes.MethodsMembranes were obtained from eyes undergoing pars plana vitrectomy for complicated proliferative diabetic retinopathy or idiopathic epiretinal membrane. Through standard immunohistochemical techniques, we labeled membranes to explore the distribution of endothelin-1 and endothelin receptor B, comparing proliferative diabetic retinopathy and idiopathic epiretinal membranes. In addition, membranes were also labeled with markers for fibroblasts, endothelial, and glial cells and studied with confocal laser scanning microscopy. The intensity of endothelin-1 labeling was quantified using standard image analysis software.ResultsFourteen membranes were included in the analysis, nine from eyes with proliferative diabetic retinopathy and five idiopathic membranes. Flatmount diabetic membranes showed co-localization of endothelin-1 with S100A4 and CD31. Immunohistochemistry and quantitative analysis of cross-sectional membranes showed significantly higher endothelin-1 labeling in proliferative diabetic retinopathy membranes compared to idiopathic membranes (p<0.05). Diabetic membranes showed more elements staining positive for S100A4 compared to idiopathic membranes.ConclusionEpiretinal membrane formation in proliferative diabetic retinopathy involves higher tissue levels of endothelin-1 and fibroblastic activity. Furthermore, endothelin-1, endothelial and fibroblastic staining appear to be correlated, suggestive of endothelial-to-mesenchymal transition in proliferative diabetic retinopathy.
Highlights
Diabetic retinopathy (DR) is a major cause of blindness worldwide and is prevalent in almost 80% of diabetics after 10 years of diabetes [1]
Immunohistochemistry and quantitative analysis of cross-sectional membranes showed significantly higher endothelin-1 labeling in proliferative diabetic retinopathy membranes compared to idiopathic membranes (p
In Proliferative diabetic retinopathy (PDR), angiogenesis and subsequent fibrosis on the retinal surface often result in the formation of fibrovascular, tractional epiretinal membranes, which lead to vision threatening complications such as tractional retinal detachment and vision loss [2,3,4,5]
Summary
Diabetic retinopathy (DR) is a major cause of blindness worldwide and is prevalent in almost 80% of diabetics after 10 years of diabetes [1]. Pericytes, involved in maintaining the blood-retinal barrier, are affected early in DR, compromising the endothelial cells and initiating a cascade of microvascular changes including microaneurysms and capillary occlusion in early stages of non-proliferative DR [2]. Proliferative diabetic retinopathy (PDR) is a late stage manifestation of DR, where progressive retinal ischemia leads to elaboration of angiogenic factors, including VEGF, with ultimate growth of new blood vessels along the interface between the retina and the vitreous humor. Recent studies have shown that the epiretinal membranes and vitreous of patients with PDR contain different protein marker patterns than non-diabetic tissues [6,7,8,9,10]. ET-1 and its receptor ETA have been shown to mediate decreased retinal blood flow during hyperglycemia and in DR [13]. In the initial stages of DR, ET-1 appears to mediate pericyte death via ETA receptors [5]
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