机构：[1]Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.[2]Department of Ophthalmology, Biomaterial and Tissue Engineering Center, Institute of Engineering in Medicine and Institute for Genomic Medicine, University of California, San Diego , La Jolla, California 92093, United States.[3]State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, 200032, China.[4]Shanghai Key Laboratory of Fundus Disease and Eye Research Institute, Shanghai JiaoTong University , Shanghai 200080, China.[5]Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Sichuan 610041, China.四川大学华西医院[6]Veterans Administration Healthcare System , San Diego, California 92161, United States.
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 α5β1 is a transmembrane receptor that binds matrix macromolecules and proteinases to stimulate angiogenesis. We recently demonstrated that integrin α5β1 plays a critical role in the development of choroidal neovascularization. In this study, we determined the role and underlying mechanisms of integrin α5β1 in angiogenesis in human choroidal endothelial cells and evaluated the antiangiogenic effects of delivering a combination therapy of ATN-161, an integrin α5β1 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 α5β1 signaling pathway. Our results indicate that fibronectin binds to integrin α5β1 and synergizes VEGF-induced angiogenesis via two independent signaling pathways, FN/integrin α5β1/FAK/ERK1/2 and FN/integrin α5β1/FAK/AKT. Integrin α5 knockdown by shRNA inhibits endothelial cell migration, tube formation, and proliferation, while ATN-161 only partially decreases integrin α5 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 α5β1 is involved in ocular pathological neovascularization in vivo, suggesting that dual inhibition of integrin α5β1 and VEGF may be a promising novel therapeutic strategy for CNV in wet AMD.
基金：
This study was supported by the National Natural
Science Foundation of China Grant (81300778, 81425006) and
Shanghai Key Basic Research Grant (11JC141601), 863
Program (2014AA021604) , and 973 Program (2012CB917304), International Cooperation Project from
Science and Technology Commission of Shanghai Municipality
(14430721600).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2016]版：
大类|2 区医学
小类|2 区医学：研究与实验2 区药学
最新[2023]版：
大类|2 区医学
小类|2 区药学3 区医学：研究与实验
第一作者：
第一作者机构：[1]Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.[2]Department of Ophthalmology, Biomaterial and Tissue Engineering Center, Institute of Engineering in Medicine and Institute for Genomic Medicine, University of California, San Diego , La Jolla, California 92093, United States.
通讯作者：
通讯机构：[1]Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.[2]Department of Ophthalmology, Biomaterial and Tissue Engineering Center, Institute of Engineering in Medicine and Institute for Genomic Medicine, University of California, San Diego , La Jolla, California 92093, United States.[4]Shanghai Key Laboratory of Fundus Disease and Eye Research Institute, Shanghai JiaoTong University , Shanghai 200080, China.[5]Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Sichuan 610041, China.[6]Veterans Administration Healthcare System , San Diego, California 92161, United States.[*1]Department of Ophthalmology, Shanghai First People’s Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, 20080, China[*2]Department of Ophthalmology, Biomaterial and Tissue Engineering Center, Institute of Engineering in Medicine and Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.
推荐引用方式(GB/T 7714)：
Wang Wen-Qiu,Wang Feng-Hua,Qin Wen-Xin,et al.Joint Antiangiogenic Effect of ATN-161 and Anti-VEGF Antibody in a Rat Model of Early Wet Age-Related Macular Degeneration.[J].Molecular pharmaceutics.2016,13(9):2881-90.doi:10.1021/acs.molpharmaceut.6b00056.
APA：
Wang Wen-Qiu,Wang Feng-Hua,Qin Wen-Xin,Liu Hai-Yun,Lu Bing...&Sun Xiao-Dong.(2016).Joint Antiangiogenic Effect of ATN-161 and Anti-VEGF Antibody in a Rat Model of Early Wet Age-Related Macular Degeneration..Molecular pharmaceutics,13,(9)
MLA：
Wang Wen-Qiu,et al."Joint Antiangiogenic Effect of ATN-161 and Anti-VEGF Antibody in a Rat Model of Early Wet Age-Related Macular Degeneration.".Molecular pharmaceutics 13..9(2016):2881-90
