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Sci Adv. 2019 Feb 13;5(2):eaau6732. doi: 10.1126/sciadv.aau6732. eCollection 2019 Feb.

Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration.

Kim J1,2,3, Park JR4,5, Choi J1,2, Park I1,2, Hwang Y5,6, Bae H1,2, Kim Y4,5, Choi W5, Yang JM2, Han S1, Chung TY3, Kim P5,6, Kubota Y7, Augustin HG8,9, Oh WY4,5, Koh GY1,2.

Author information

1
Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.
2
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
3
Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
4
Department of Mechanical Engineering, KAIST, Daejeon 34141, Republic of Korea.
5
KI for Health Science and Technology (KIHST), KAIST, Daejeon 34141, Republic of Korea.
6
Graduate School of Nanoscience and Technology, KAIST, Daejeon 34141, Republic of Korea.
7
The Laboratory of Vascular Biology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
8
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.
9
Division of Vascular Oncology and Metastasis, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg 69121, Germany.

Abstract

Choriocapillary loss is a major cause of neovascular age-related macular degeneration (NV-AMD). Although vascular endothelial growth factor (VEGF) blockade for NV-AMD has shown beneficial outcomes, unmet medical needs for patients refractory or tachyphylactic to anti-VEGF therapy exist. In addition, the treatment could exacerbate choriocapillary rarefaction, necessitating advanced treatment for fundamental recovery from NV-AMD. In this study, Tie2 activation by angiopoietin-2-binding and Tie2-activating antibody (ABTAA) presents a therapeutic strategy for NV-AMD. Conditional Tie2 deletion impeded choriocapillary maintenance, rendering eyes susceptible to NV-AMD development. Moreover, in a NV-AMD mouse model, ABTAA not only suppressed choroidal neovascularization (CNV) and vascular leakage but also regenerated the choriocapillaris and relieved hypoxia. Conversely, VEGF blockade degenerated the choriocapillaris and exacerbated hypoxia, although it suppressed CNV and vascular leakage. Together, we establish that angiopoietin-Tie2 signaling is critical for choriocapillary maintenance and that ABTAA represents an alternative, combinative therapeutic strategy for NV-AMD by alleviating anti-VEGF adverse effects.

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