Abstract
Choroidal neovascularization(CNV) is the most severe complication in Age-related macular degeneration(AMD) and the most common cause of irreversible blindness in the elderly in developed world. The aim of this study was to identify the effect of transforming growth factor-β(TGF-β) and Smad2/3-VEGF/TNF-α signaling on CNV angiopoiesis, and to explore TGF-β inhibitors on the development of CNV in a CNV mouse model. Fundus fluorescein angiography(FFA) was used to evaluate the laser-induced CNV formation. The histology of CNV lesions stained with hematoxylin-eosin(HE) was obtained. The immunofluorescent staining was performed to determine TGF-β protein expression. The expressions of TGF-β, phosphorylated Smad2/3, VEGF and TNF-α were determined by using Western blot analysis. The CNV areas were analyzed by using fluorescein stain on RPE/choroid-sclera flat mounts. We found the levels of TGF-β protein expression increasingly reached the peak till 3rd week during the CNV development. The protein levels of VEGF and TNF-α also increased significantly in CNV mice, which were inhibited by a synthetic TGF-β inhibitor LY2157299 or a natural TGF-β inhibitor Decorin. The phosphorylated Smad2/3 levels increased significantly in CNV mice, but this response was profoundly suppressed by the TGF-β inhibitors. Here we have demonstrated that TGF-β/Smad signaling plays an important role in Laser-induced CNV formation through down-regulation of VEGF and TNF-α expressions, suggesting TGF-β inhibitors may provide an alternative to traditional methods in wet AMD treatment.
Highlights
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness and an improving public health problem due to aging population in the developed world[1, 2]
Understanding the mechanisms of choroid neovascularization (CNV) etiopathology could have a better impact on the health and quality of life of patients with wet AMD
As Laser-induced CNV by a rupture of Bruch’s membrane shares many of the same pathologic steps with neovascularization arises from varied causes, we utilized this in vivo model to evaluate the effect of TGF-β signaling pathway because it has been shown to possess some actions including inflammatory and angiogenesis
Summary
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness and an improving public health problem due to aging population in the developed world[1, 2]. CNV angiopoiesis is a series of complex pathological processes and still remains unclear, experimental and clinical studies have revealed that a variety of cytokines, chemokines and endothelial adhesion molecules play crucial roles in the development of CNV7–9. Several angiogenic factors, such as vascular endothelial www.nature.com/scientificreports/. Considering the crucial roles of TGF-β in neovascularization, we hypothesize that TGF-β may work in concert with other cytokines in VEGF up-regulation, and selective blockade of TGF-β would abate CNV development To test this hypothesis, the Laser photocoagulation was applied to establish the experimental CNV mouse model to mimic wet AMD. We found that TGF-β/Smad pathway through regulation of pro-angiogenic factors played a critical role in the development of experimental CNV, suggesting TGF-β/Smad signaling pathway blockage may provide a novel, effective auxiliary treatment for AMD
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