title: Adrenomedullin-RAMP2 system is crucially involved in retinal angiogenesis.
abstract: Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilating molecule. We previously showed that in mice, homozygous knockout of ADM (ADM(-/-)) or its receptor regulating protein, RAMP2 (RAMP2(-/-)), is embryonically lethal due to abnormal vascular development, thereby demonstrating the importance of ADM and its receptor signaling to vascular development. ADM expression in the retina is strongly induced by ischemia; however, its role in retinal pathophysiology remains unknown. Here, we analyzed oxygen-induced retinopathy (OIR) using heterozygous ADM and RAMP2 knockout mice models (ADM(+/-) or RAMP2(+/-), respectively). In addition, we analyzed the role of the ADM-RAMP2 system during earlier stages of retinal angiogenesis using an inducible endothelial cell-specific RAMP2 knockout mouse line (DI-E-RAMP2(-/-)). Finally, we assessed the ability of antibody-induced ADM blockade to control pathological retinal angiogenesis in OIR. In OIR, neovascular tufts, avascular zones, and hypoxic areas were all smaller in ADM(+/-) retinas compared with wild-type mice. ADM(+/-) retinas also exhibited reduced levels of VEGF and eNOS expression. DI-E-RAMP2(-/-) showed abnormal retinal vascular patterns in the early stages of development. However, ADM enhanced the proliferation and migration of retinal endothelial cells. Finally, we found intravitreal injection of anti-ADM antibody reduced pathological retinal angiogenesis. In conclusion, the ADM-RAMP2 system is crucially involved in retinal angiogenesis. ADM and its receptor system are potential therapeutic targets for controlling pathological retinal angiogenesis.
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Iesato
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Toriyama
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakurai
authors.forename: Akiko
authors.initials: A
authors.lastname: Kamiyoshi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ichikawa-Shindo
authors.forename: Hisaka
authors.initials: H
authors.lastname: Kawate
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Teruhide
authors.initials: T
authors.lastname: Koyama
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Uetake
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Megumu
authors.initials: M
authors.lastname: Tanaka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Igarashi
authors.forename: Toshinori
authors.initials: T
authors.lastname: Murata
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
mesh_terms: D053607:Adrenomedullin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D047109:Fetal Development / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D058449:Intravitreal Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D058263:Receptor Activity-Modifying Protein 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D012171:Retinal Vessels / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; C545506:Ramp2 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D053607:Adrenomedullin