title: Joint Antiangiogenic Effect of ATN-161 and Anti-VEGF Antibody in a Rat Model of Early Wet Age-Related Macular Degeneration.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.|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.
authors.forename: Wen-Qiu
authors.initials: WQ
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, 200032, China.
authors.forename: Wen-Xin
authors.initials: WX
authors.lastname: Qin
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of Fundus Disease and Eye Research Institute, Shanghai JiaoTong University , Shanghai 200080, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gu
authors.affiliation: 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.|Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Sichuan 610041, China.
authors.forename: William
authors.initials: W
authors.lastname: Shi
authors.affiliation: 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.|Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Sichuan 610041, China.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wen
authors.affiliation: 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.
authors.forename: Frances
authors.initials: F
authors.lastname: Wu
authors.affiliation: 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.|Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Sichuan 610041, China.|Veterans Administration Healthcare System , San Diego, California 92161, United States.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.|Shanghai Key Laboratory of Fundus Disease and Eye Research Institute, Shanghai JiaoTong University , Shanghai 200080, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Sun
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000188:drug therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008268:Macular Degeneration / Q000188:drug therapy*; D008297:Male; D011485:Protein Binding; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D005353:Fibronectins; D039081:Integrin alpha5beta1; D042461:Vascular Endothelial Growth Factor A
keywords: VEGF; age-related macular degeneration; choroidal neovascularization; extracellular matrix; integrin