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

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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 (αCGRP and βCGRP), 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. αCGRP was found to have a potent vascular relaxant activity compared with βCGRP 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. αCGRP and βCGRP equally suppressed the production of TNF-α 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.