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Joint Antiangiogenic Effect of ATN-161 and Anti-VEGF Antibody in a Rat Model of Early Wet Age-Related Macular Degeneration.
Wang, Wen-Qiu; Wang, Feng-Hua; Qin, Wen-Xin; Liu, Hai-Yun; Lu, Bing; Chung, Christopher; Zhu, Jie; Gu, Qing; Shi, William; Wen, Cindy; Wu, Frances; Zhang, Kang; Sun, Xiao-Dong.
Afiliação
  • Wang WQ; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.
  • Wang FH; 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.
  • Qin WX; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.
  • Liu HY; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, 200032, China.
  • Lu B; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.
  • Chung C; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University , Shanghai, 20080, China.
  • Zhu J; 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.
  • Gu Q; 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.
  • Shi W; Shanghai Key Laboratory of Fundus Disease and Eye Research Institute, Shanghai JiaoTong University , Shanghai 200080, China.
  • Wen C; 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.
  • Wu F; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Sichuan 610041, China.
  • Zhang K; 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.
  • Sun XD; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Sichuan 610041, China.
Mol Pharm ; 13(9): 2881-90, 2016 09 06.
Article em En | MEDLINE | ID: mdl-27089240
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 α5ß1 is a transmembrane receptor that binds matrix macromolecules and proteinases to stimulate angiogenesis. We recently demonstrated that integrin α5ß1 plays a critical role in the development of choroidal neovascularization. In this study, we determined the role and underlying mechanisms of integrin α5ß1 in angiogenesis in human choroidal endothelial cells and evaluated the antiangiogenic effects of delivering a combination therapy of ATN-161, an integrin α5ß1 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 α5ß1 signaling pathway. Our results indicate that fibronectin binds to integrin α5ß1 and synergizes VEGF-induced angiogenesis via two independent signaling pathways, FN/integrin α5ß1/FAK/ERK1/2 and FN/integrin α5ß1/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 α5ß1 is involved in ocular pathological neovascularization in vivo, suggesting that dual inhibition of integrin α5ß1 and VEGF may be a promising novel therapeutic strategy for CNV in wet AMD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores da Angiogênese / Integrina alfa5beta1 / Fator A de Crescimento do Endotélio Vascular / Degeneração Macular / Anticorpos Monoclonais Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores da Angiogênese / Integrina alfa5beta1 / Fator A de Crescimento do Endotélio Vascular / Degeneração Macular / Anticorpos Monoclonais Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: China