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

Am J Pathol. 2021 Apr;191(4):652-668. doi: 10.1016/j.ajpath.2020.12.012. Epub 2020 Dec 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / metabolism*
  • Animals
  • Choroidal Neovascularization / metabolism
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / physiology
  • Fibrosis / metabolism
  • Humans
  • Intravitreal Injections / methods
  • Macular Degeneration / metabolism*
  • Macular Degeneration / pathology*
  • Mice, Knockout
  • Receptor Activity-Modifying Protein 2 / genetics
  • Receptor Activity-Modifying Protein 2 / metabolism*
  • Retinal Pigment Epithelium / metabolism

Substances

  • RAMP2 protein, human
  • Ramp2 protein, mouse
  • Receptor Activity-Modifying Protein 2
  • Adrenomedullin