Abstract |
Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti- vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-β and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-β and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition.
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Authors | Masaaki Tanaka, Shinji Kakihara, Kazutaka Hirabayashi, Akira Imai, Yuichi Toriyama, Yasuhiro Iesato, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Megumu Tanaka, Nanqi Cui, Yangxuan Wei, Yunlu Zhao, Kohsuke Aruga, Akihiro Yamauchi, Toshinori Murata, Takayuki Shindo |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 191
Issue 4
Pg. 652-668
(04 2021)
ISSN: 1525-2191 [Electronic] United States |
PMID | 33385343
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- RAMP2 protein, human
- Ramp2 protein, mouse
- Receptor Activity-Modifying Protein 2
- Adrenomedullin
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Topics |
- Adrenomedullin
(metabolism)
- Animals
- Choroidal Neovascularization
(metabolism)
- Disease Models, Animal
- Epithelial-Mesenchymal Transition
(physiology)
- Fibrosis
(metabolism)
- Humans
- Intravitreal Injections
(methods)
- Macular Degeneration
(metabolism, pathology)
- Mice, Knockout
- Receptor Activity-Modifying Protein 2
(genetics, metabolism)
- Retinal Pigment Epithelium
(metabolism)
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