Adrenomedullin inhibits choroidal neovascularization via CCL2 in the retinal pigment epithelium

Am J Pathol. 2012 Oct;181(4):1464-72. doi: 10.1016/j.ajpath.2012.06.028. Epub 2012 Jul 27.


The molecular mechanism that leads to age-related macular degeneration (AMD) is poorly understood. Gene expression profiling identified adrenomedullin (ADM) as a possible molecular target for the treatment of AMD and expression of ADM was upregulated in eyes with laser-induced choroidal neovascularization (CNV). In vivo experiments strongly indicated that ADM inhibits laser-induced CNV. In vitro tube formation assay demonstrated that neither ADM nor conditioned medium from the retinal pigment epithelial (RPE) cells, D407 cells, treated with ADM affected the capillary-formation of human umbilical vein endothelial cells. In contrast, in vitro macrophage migration assay clearly demonstrated that the conditioned medium of D407 inhibited macrophage migration. Furthermore, the expression of C-C motif chemokine 2 (CCL2) was significantly inhibited in D407 cells after ADM treatment. In vivo experiments using a laser-induced CNV model in ADM(+/-) mice demonstrated that CCL2 expression was upregulated in ADM(+/-) mice with concomitant increase in macrophage migration in the subretinal space. Additionally, the effect of ADM was abrogated in CCL2 knockout mice. These results suggest that administration of ADM inhibits macrophage migration in the subretinal space and leads to the suppression of laser-induced CNV in an animal model. The inhibition of macrophage migration occurred through the CCL2 from RPE. This study provides a novel potential therapeutic target for AMD which does not substantially disrupt VEGF-A signaling mediated vasculogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / genetics
  • Adrenomedullin / metabolism*
  • Animals
  • Cell Movement
  • Chemokine CCL2 / metabolism*
  • Choroid / blood supply
  • Choroid / metabolism
  • Choroid / pathology
  • Choroidal Neovascularization / genetics
  • Choroidal Neovascularization / pathology*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Gene Expression Regulation
  • Humans
  • Lasers
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retinal Pigment Epithelium / blood supply*
  • Retinal Pigment Epithelium / metabolism*
  • Retinal Pigment Epithelium / pathology


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • RNA, Messenger
  • Adrenomedullin