title: An angiogenic role for adrenomedullin in choroidal neovascularization.
abstract: OBJECTIVE
  Adrenomedullin (ADM) has been shown to take part in physiological and pathological angiogenesis. The purpose of this study was to investigate whether ADM signaling is involved in choroidal neovascularization (CNV) using a mouse model.
  
  
  RESULTS
  CNV was induced by laser photocoagulation in 8-week-old C57BL/6 mice. ADM mRNA expression significantly increased following treatment, peaking 4 days thereafter. The expression of ADM receptor (ADM-R) components (CRLR, RAMP2 and RAMP 3) was higher in CD31(+)CD45(-) endothelial cells (ECs) than CD31(-)CD45(-) non-ECs. Inflammatory stimulation upregulated the expression of ADM not only in cell lines but also in cells in primary cultures of the choroid/retinal pigment epithelium complex. Supernatants from TNFα-treated macrophage cell lines potentiated the proliferation of ECs and this was partially suppressed by an ADM antagonist, ADM (22-52). Intravitreous injection of ADM (22-52) or ADM neutralizing monoclonal antibody (mAb) after laser treatment significantly reduced the size of CNV compared with vehicle-treated controls (p<0.01).
  
  
  CONCLUSIONS
  ADM signaling is involved in laser-induced CNV formation, because both an ADM antagonist and ADM mAb significantly inhibited it. Suppression of ADM signaling might be a valuable alternative treatment for CNV associated with age-related macular degeneration.
authors.affiliation: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakimoto
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kidoya
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kamei
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Naito
authors.forename: Daishi
authors.initials: D
authors.lastname: Yamakawa
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sakaguchi
authors.forename: Taku
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Kohji
authors.initials: K
authors.lastname: Nishida
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
mesh_terms: D053607:Adrenomedullin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007834:Lasers / Q000009:adverse effects; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D058263:Receptor Activity-Modifying Protein 2 / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C545506:Ramp2 protein, mouse; C545507:Ramp3 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D014409:Tumor Necrosis Factor-alpha; D053607:Adrenomedullin; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse