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Igarashi K.,Shinshu University | Sakurai T.,Shinshu University | Kamiyoshi A.,Shinshu University | Ichikawa-Shindo Y.,Shinshu University | And 13 more authors.
Peptides | Year: 2014

The accessory protein RAMP2 is a component of the CLR/RAMP2 dimeric adrenomedullin (AM) receptorand is the primary determinant of the vascular functionality of AM. RAMP2 is highly expressed in thebrain; 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 endoge-nous AM-RAMP2 system in cerebral ischemia. To induce acute or chronic ischemia, mice were subjectedto middle cerebral artery occlusion (MCAO) or bilateral common carotid artery stenosis (BCAS), respec-tively. In RAMP2+/? mice subjected to MCAO, recovery of cerebral blood flow (CBF) was slower than inWT mice. AM gene expression was upregulated after infarction in both genotypes, but the increase wasgreater 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, recov-ery 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 alsoshowed greater reductions in nerve cells and less compensatory capillary growth than WT mice. Theseresults indicate the AM-RAMP2 system works to protect nerve cells from both acute and chronic cerebralischemia by maintaining CBF, suppressing oxidative stress, and in the case of chronic ischemia, enhancingcapillary growth. © 2014 Elsevier Ltd. All rights reserved.

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