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Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration.

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.
AuthorsMasaaki 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
JournalThe American journal of pathology (Am J Pathol) Vol. 191 Issue 4 Pg. 652-668 (04 2021) ISSN: 1525-2191 [Electronic] United States
PMID33385343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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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