title: Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia.
abstract: The accessory protein RAMP2 is a component of the CLR/RAMP2 dimeric adrenomedullin (AM) receptor and is the primary determinant of the vascular functionality of AM. RAMP2 is highly expressed in the brain; however, its function there remains unclear. We therefore used heterozygous RAMP2 knockout (RAMP2+/-) mice, in which RAMP2 expression was reduced by half, to examine the actions of the endogenous AM-RAMP2 system in cerebral ischemia. To induce acute or chronic ischemia, mice were subjected to middle cerebral artery occlusion (MCAO) or bilateral common carotid artery stenosis (BCAS), respectively. In RAMP2+/- mice subjected to MCAO, recovery of cerebral blood flow (CBF) was slower than in WT mice. AM gene expression was upregulated after infarction in both genotypes, but the increase was greater in RAMP2+/- mice. Pathological analysis revealed severe nerve cell death and demyelination, and a higher level of oxidative stress in RAMP2+/- mice. In RAMP2+/- mice subjected to BCAS, recovery of cerebral perfusion was slower and less complete than in WT mice. In an 8-arm radial maze test, RAMP2+/- mice required more time to solve the maze and showed poorer reference memory. They also showed greater reductions in nerve cells and less compensatory capillary growth than WT mice. These results indicate the AM-RAMP2 system works to protect nerve cells from both acute and chronic cerebral ischemia by maintaining CBF, suppressing oxidative stress, and in the case of chronic ischemia, enhancing capillary growth.
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kamiyoshi
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ichikawa-Shindo
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Hisaka
authors.initials: H
authors.lastname: Kawate
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Toriyama
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Megumu
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Xian
authors.initials: X
authors.lastname: Xian
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Imai
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Liuyu
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Owa
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Teruhide
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Uetake
authors.affiliation: Department of Regenerative Medicine, Research Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan. Electronic address: tshindo@shinshu-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
mesh_terms: D053607:Adrenomedullin / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000254:growth & development / Q000473:pathology; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics* / Q000503:physiopathology; D016893:Carotid Stenosis / Q000378:metabolism / Q000503:physiopathology; D016923:Cell Death / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D058263:Receptor Activity-Modifying Protein 2 / Q000096:biosynthesis / Q000235:genetics*; D058265:Receptors, Adrenomedullin / Q000235:genetics* / Q000378:metabolism
chemical_list: C545503:RAMP2 protein, human; D058263:Receptor Activity-Modifying Protein 2; D058265:Receptors, Adrenomedullin; D053607:Adrenomedullin
keywords: Adrenomedullin; Blood vessel; Cerebral ischemia; Receptor activity-modifying protein