Department of Biochemistry, Faculty of Medicine, Universidad Nacional Autónoma de México, Av. Universidad 3000, 04510, Mexico City, Mexico; Cell and Tissue Biology, Research Unit, Institute of Ophthalmology, Conde de Valenciana, Chimalpopoca 14, 06800, Mexico City, Mexico.
Cell and Tissue Biology, Research Unit, Institute of Ophthalmology, Conde de Valenciana, Chimalpopoca 14, 06800, Mexico City, Mexico.
Exp Eye Res. 2020 Apr;193:107977. doi: 10.1016/j.exer.2020.107977. Epub 2020 Feb 17.
Corneal neovascularization (CNV) is a common sight-threatening pathology that can be induced by a variety of inflammatory and angiogenic stimuli. Current CNV treatments include anti-inflammatory drugs and antibody-based inhibitors of vascular endothelial growth factor (VEGF). However, these are not always effective and novel therapeutic approaches are needed. Previous work has indicated a role for nucleolin (NCL) in VEGF-mediated neoangiogenesis in a suture-induced CNV model. The major goal for this current study is to test the effect of AS1411, a NCL-binding DNA aptamer that has reached human clinical trials, on neovascularization in a murine model of VEGF-mediated CNV. Our results show that topical administration of AS1411 can significantly inhibit corneal neovascularization in this model. Mechanistic studies indicate that AS1411 reduces the VEGF-stimulated proliferation, migration, and tube formation of primary cells obtained from human limbus stroma (HLSC). AS1411 treatment also significantly reduced VEGF-stimulated induction of miR-21 and miR-221 in HLSC, suggesting a role for these pro-angiogenic miRNAs in mediating the effects of AS1411 in this system. In sum, this new research further supports a role for NCL in the molecular etiology of CNV and identifies AS1411 as a potential anti-angiogenic CNV treatment that works by a novel mechanism of action.
角膜新生血管（CNV）是一种常见的威胁视力的病理，可由多种炎症和血管生成刺激引起。目前的 CNV 治疗方法包括抗炎药物和血管内皮生长因子（VEGF）的抗体抑制剂。然而，这些并不总是有效，需要新的治疗方法。先前的工作表明核仁素（NCL）在缝合线诱导的 CNV 模型中 VEGF 介导的新血管生成中起作用。本研究的主要目标是测试 AS1411（一种已进入人体临床试验的 NCL 结合 DNA 适体）对 VEGF 介导的 CNV 小鼠模型中新生血管形成的影响。我们的结果表明，局部给予 AS1411 可显著抑制该模型中的角膜新生血管形成。机制研究表明，AS1411 可减少原代人角膜缘基质细胞（HLSC）中 VEGF 刺激的增殖、迁移和管形成。AS1411 处理还显著降低了 HLSC 中 VEGF 刺激的 miR-21 和 miR-221 的诱导，表明这些促血管生成 miRNA 在介导 AS1411 在该系统中的作用中起作用。总之，这项新研究进一步支持 NCL 在 CNV 的分子发病机制中的作用，并确定 AS1411 是一种潜在的抗血管生成 CNV 治疗方法，其作用机制新颖。
