title: Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice.
abstract: Calcitonin gene-related peptide (CGRP) is thought to be a prominent neuropeptide in cardiovascular regulation and neuroimmune modulation. There are two isoforms of CGRP (alphaCGRP and betaCGRP), and the main CGRP receptors are probably composed of a calcitonin receptor-like receptor (CLR) and a receptor activity-modifying protein (RAMP)1. However, the physiological functions of CGRP that are mediated through the CLR/RAMP1 receptors remain to be clarified. For an improved understanding of the functions, we generated mice deficient in RAMP1, a specific subunit of CGRP receptors, by a conditional gene-targeting technique. The RAMP1-deficient mice (RAMP1(-/-)) exhibited high blood pressure, with no changes in heart rate. alphaCGRP was found to have a potent vascular relaxant activity compared with betaCGRP in the artery of the WT (RAMP1(+/+)) mice. The activities of both CGRP isoforms were remarkably suppressed in the arteries of the RAMP1(-/-) mice. The LPS-induced inflammatory responses of the RAMP1(-/-) mice revealed a transient and significant increase in the serum CGRP levels and high serum levels of proinflammatory cytokines compared with the RAMP1(+/+) mice. alphaCGRP and betaCGRP equally suppressed the production of TNF-alpha and IL-12 in bone marrow-derived dendritic cells stimulated with lipopolysaccharide. Their inhibitory effects were not observed in the bone marrow-derived dendritic cells of the RAMP1(-/-) mice. These results indicate that CGRP signaling through CLR/RAMP1 receptors plays a crucial role in the regulation of both blood pressure by vascular relaxation and proinflammatory cytokine production from dendritic cells.
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan. tujikawa@phs.osaka-u.ac.jp
authors.forename: Kazutake
authors.initials: K
authors.lastname: Tsujikawa
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yayama
authors.forename: Tamon
authors.initials: T
authors.lastname: Hayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsushita
authors.forename: Taijiro
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shigeno
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ogitani
authors.forename: Megumi
authors.initials: M
authors.lastname: Hirayama
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kato
authors.forename: So-ichiro
authors.initials: S
authors.lastname: Fukada
authors.forename: Shingo
authors.initials: S
authors.lastname: Takatori
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D001853:Bone Marrow / Q000276:immunology; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D006973:Hypertension / Q000235:genetics*; D007249:Inflammation / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics / Q000502:physiology; D014664:Vasodilation / Q000235:genetics
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide