• Proc. Natl. Acad. Sci. U.S.A. · Oct 2007

    Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice.

    • Kazutake Tsujikawa, Katsutoshi Yayama, Tamon Hayashi, Hiroaki Matsushita, Taijiro Yamaguchi, Tomomi Shigeno, Yusuke Ogitani, Megumi Hirayama, Tetsuya Kato, So-ichiro Fukada, Shingo Takatori, Hiromu Kawasaki, Hiroshi Okamoto, Masahito Ikawa, Masaru Okabe, and Hiroshi Yamamoto.
    • Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan. tujikawa@phs.osaka-u.ac.jp
    • Proc. Natl. Acad. Sci. U.S.A. 2007 Oct 16;104(42):16702-7.

    AbstractCalcitonin 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.

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