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Regulation of Adrenomedullin and its Family Peptide by RAMP System - Lessons from Genetically Engineered Mice Shindo, Takayuki Sakurai, Takayuki Kamiyoshi, Akiko Ichikawa-Shindo, Yuka Shimoyama, Natsumi Iinuma, Nobuyoshi Arai, Takuma Miyagawa, Shinichi © 2013 Bentham Science Publishers Adrenomedullin receptor activity-modifying proteins knockout mouse angiogenesis lymphangiogenesis endothelial cell Adrenomedullin (ADM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic molecule involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. Homozygotes of ADM knockout mice (ADM-/-) were lethal at mid-gestation with abnormalities of vascular development and this finding clarified the angiogenic potency of ADM. Calcitonin gene-related peptide (CGRP), which has a structure and function similar to that of ADM, has been identified as a family peptide of ADM. Unlike ADM-/-, CGRP-/- were apparently normal. Therefore, the study of knockout mice first clarified the distinctly different physiological roles between ADM and CGRP. In contrast, heterozygotes of ADM knockout mice (ADM+/-) were alive but showed blood pressure elevation, reduced neovascularization, and enhanced neointimal formation by arterial injury. Based on these observations, there was hope ADM would have a therapeutic use. However, ADM has a short half-life in the blood stream and its application in chronic disease has limitations. Therefore, we focused on the ADM receptor system. The calcitonin-receptor-like receptor (CLR), which is the ADM receptor, associates with one of the accessory proteins, called receptor activity-modifying proteins (RAMPs). By interacting with RAMP1, CLR exhibits a high affinity for CGRP, whereas by interacting with either RAMP2 or -3, CLR exhibits a high affinity for ADM. We generated RAMP knockout mice and found that vascular phenotypes similar to ADM-/- were reproduced only in RAMP2-/-. This shows that RAMP2 is the key determinant of the vascular functions of ADM. RAMP2 could be an attractive therapeutic target in cardiovascular diseases. BENTHAM SCIENCE PUBL LTD 2013-08 jpn journal article AM http://hdl.handle.net/10091/00020112 https://soar-ir.repo.nii.ac.jp/records/19351 https://pubmed.ncbi.nlm.nih.gov/23745699 23745699 https://doi.org/10.2174/13892037113149990052 10.2174/13892037113149990052 1389-2037 AA11692455 CURRENT PROTEIN & PEPTIDE SCIENCE 14 5 347 357 https://soar-ir.repo.nii.ac.jp/record/19351/files/Regulation_ Adrenomedullin_its_Family_Peptide_RAMP_System.pdf application/pdf 1.7 MB 2017-12-28