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wenqiu wang, Xiaodong Sun; Integrin α5β1 promotes VEGF-induced angiogenesis through activating FAK-mediated PI3K/AKT and ERK1/2 pathways. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1953.
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This study was designed to determine the role and underlying mechanisms of integrin α5β1 in angiogenesis in human choroidal endothelial cells (hCECs), and to evaluate the anti-angiogenic effects of combined therapy of ATN-161 (AC-PHSCN-NH2), an integrinα5β1 inhibitor, and anti-VEGF mAb in laser-induced CNV in experimental rats.
The antiangiogenic potential of ATN-161 was evalu-ated in VEFG-stimulated hCECs by MTS proliferation assays,migration assays, and synthetic matrix capillary tube formation assays. To evaluate the antiangiogenic effects of ATN-161 in vivo, CNV was induced in rats by laser photocoagulation. ATN-161, AF564 anti-VEGF antibody, combined regeants were injected intravitreally immediately after photocoagula-tion. Eyes were examined by SD-OCT and fluorescein an-giography on days 1, 7, and 14 after injection, and the areas of CNV were measured by analysis of choroidal flatmounts at day 14. We
We demonstrated that fibronectin (Fn) bound to integrin α5β1 and induced angiogenesis by increasing hCECs migration, up-regulating VEGF expression, and stimulating CD147 activity. Integrin α5β1 regulated VEGF expression via two independent downstream signaling pathways, FN/integrin α5β1/FAK/ERK1/2 and FN/integrin α5β1/FAK/AKT, followed by induction of HIF1α, c-JUN and Sp1 binding. Treatment with ATN-161 plus anti-VEGF antibody attenuated angiogenesis more effectively than either agent alone.
In summary, these results provide the first evidence for a role of Integrin α5β1 in ocular pathological neovascularization in vivo. The inhibition of Integrin α5β1 by ATN-161 may be a promising novel therapy for CNV.
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