Joint Antiangiogenic Effect of ATN-161 and Anti-VEGF Antibody in a Rat Model of Early Wet Age-Related Macular Degeneration
Joint Antiangiogenic Effect of ATN-161 and Anti-VEGF Antibody in a Rat Model of Early Wet Age-Related Macular Degeneration
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DOI：
10.1021/acs.molpharmaceut.6b00056
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发表时间：
2016-09-01
影响因子：
4.9
通讯作者：
Sun, Xiao-Dong
中科院分区：
文献类型：
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作者：
Wang, Wen-Qiu;Wang, Feng-Hua;Sun, Xiao-Dong
湿性年龄相关性黄斑变性（AMD）是美国老年人失明的主要原因，其特征在于异常血管生长，称为脉络膜新生血管形成（CNV）。整合素α 5 β 1是一种跨膜受体，其结合基质大分子和蛋白酶以刺激血管生成。我们最近证实整合素α 5 β 1在脉络膜新生血管的发展中起着关键作用。在这项研究中，我们确定了整合素α 5 β 1在人脉络膜内皮细胞血管生成中的作用和潜在机制，并评估了ATN-161、整合素α 5 β 1抑制剂和抗VEGF单克隆抗体联合治疗激光诱导的CNV大鼠的抗血管生成作用。血管内皮生长因子（VEGF）是一种信号传导蛋白，其通过与整合素α 5 β 1信号传导途径不同的途径刺激血管发生和血管生成。我们的研究结果表明，纤连蛋白结合整合素α 5 β 1和协同VEGF诱导的血管生成通过两个独立的信号通路，FN/整合素α 5 β 1/FAK/ERK 1/2和FN/整合素α 5 β 1/FAK/AKT。通过shRNA敲低整合素α 5抑制内皮细胞迁移、管形成和增殖，而ATN-161仅部分降低整合素α 5功能。用ATN-161与抗VEGF抗体组合的治疗显示出减弱血管生成的联合作用。总之，我们的研究结果提供了第一个证据的机制，其中整合素α 5 β 1参与眼部病理性新生血管形成在体内，这表明，整合素α 5 β 1和VEGF的双重抑制可能是一个有前途的新的治疗策略，在湿性AMD的CNV。
The wet form of age-related macular degeneration (AMD) is a leading cause of blindness among elderly Americans and is characterized by abnormal vessel growth, termed choroidal neovascularization (CNV). Integrin alpha 5 beta 1 is a transmembrane receptor that binds matrix macromolecules and proteinases to stimulate angiogenesis. We recently demonstrated that integrin alpha 5 beta 1 plays a critical role in the development of choroidal neovascularization. In this study, we determined the role and underlying mechanisms of integrin alpha 5 beta 1 in angiogenesis in human choroidal endothelial cells and evaluated the antiangiogenic effects of delivering a combination therapy of ATN-161, an integrin alpha 5 beta 1 inhibitor, and an anti-VEGF monoclonal antibody to rats with laser induced CNV. Vascular endothelial growth factor (VEGF) is a signaling protein that stimulates vasculogenesis and angiogenesis through a pathway that is distinct from the integrin alpha 5 beta 1 signaling pathway. Our results indicate that fibronectin binds to integrin alpha 5 beta 1 and synergizes VEGF-induced angiogenesis via two independent signaling pathways, FN/integrin alpha 5 beta 1/FAK/ERK1/2 and FN/integrin alpha 5 beta 1/FAK/AKT. Integrin alpha 5 knockdown by shRNA inhibits endothelial cell migration, tube formation, and proliferation, while ATN-161 only partially decreases integrin a5 function. Treatment with ATN-161 combined with anti-VEGF antibody showed joint effects in attenuating angiogenesis. In summary, our results provide the first evidence for the mechanisms by which integrin alpha 5 beta 1 is involved in ocular pathological neovascularization in vivo, suggesting that dual inhibition of integrin alpha 5 beta 1 and VEGF may be a promising novel therapeutic strategy for CNV in wet AMD.