Elevated Sympathetic Nervous Activity in Mice Deficient in αCGRP

Oh-hashi, Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Imai, Tetsuo; Wang, Yuhui; Morita, Hiroyuki; Imai, Yasushi; Kayaba, Yuji; Nishimatsu, Hiroaki; Suematsu, Yoshihiro; Hirata, Yasunobu; Yazaki, Yoshio; Nagai, Ryozo; Kuwaki, Tomoyuki; Kurihara, Hiroki

doi:10.1161/hh2301.100812

Cited by 149 publications

(124 citation statements)

References 25 publications

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“…It is yet to be determined whether this NANCdependent physiological antagonism of sympathetic/ parasympathetic tone is caused by a direct vascular effect of CGRP and/or through the interference of this neuropeptide with noradrenaline/acetylcholine release from perivascular nerve terminals. In support of the latter concept, Oh-hashi et al (2001) have reported increased urinary levels of catecholamine metabolites in mice lacking the aCGRP gene. In contrast, Maynard and Burnstock (1994) have shown that purines but not CGRP act as the main pre-junctional modulator of tritiated noradrenaline release in the rabbit ear artery model.…”

Section: Discussionmentioning

confidence: 85%

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Legros

Tirapelli

Brochu

et al. 2007

British J Pharmacology

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Background and purpose: Calcitonin gene-related peptide (CGRP), a capsaicin-sensitive neuromodulator of splanchnic vascular tone in several animal species, remains poorly investigated in mouse models. We therefore assessed whether endogenous CGRP is a non-adrenergic/non-cholinergic (NANC) neuromodulator in the mesenteric vascular bed of the mouse. Experimental approach: Arterial and venous changes in perfusion pressure in response to perivascular nerve stimulation (PNS) were monitored in the mouse mesenteric bed under basal conditions or precontracted with KCl (artery) or U46619 (vein) in circuits pretreated with guanethidine, atropine, indomethacin and prazosin. Arterial responses to NANC were also characterized with a CGRP1 antagonist, haCGRP 8À37. Finally, the PNS-induced release of arterial CGRP was measured by enzyme immunoassay. Key results: HaCGRP 8À37 enhanced PNS-induced arterial increases in perfusion pressure under basal tone. PNS-induced stimulation of NANC triggered an haCGRP 8À37 or capsaicin-sensitive reduction in perfusion pressure of the pre-contracted arterial bed only. Chemical removal of the endothelium inhibited PNS-and haCGRP-induced reduction in perfusion pressure in the arterial mesenteric bed. Responses to NANC nerves were reduced by guanylate and adenylate cyclase inhibitors (1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (ODQ)) and [9-(tetrahydro-2-furanyl)-9H-purin-6-amine] (SQ 22 536), respectively. A neuronal NOS inhibitor (7-nitroindazole; 7-NI) also enhanced the response to NANC in vessels from wild-type, eNOS KO but not iNOS KO mice. Finally, PNS enhanced the release of immunoreactive CGRP from the perfused arterial mesenteric bed. Conclusions and implications: Our study demonstrates a role for CGRP in the NANC-dependent reduction in perfusion pressure of the arterial but not venous mesenteric bed of the mouse. (2007) Keywords: CGRP; haCGRP 8À37 ; neuronal nitric oxide synthase; arterial mesenteric vasculature; mouse model British Journal of Pharmacology

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Section: Discussionmentioning

confidence: 85%

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Legros

Tirapelli

Brochu

et al. 2007

British J Pharmacology

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“…Because the calcitonin gene was also knocked out in the mice, it is not certain whether the phenotypes of the mutant mice were by the loss of CGRP, calcitonin, or both. Recently, a third strain of ␣CGRP-deficient mice has been developed by Oh-hashi et al (24). The knockout mice have significantly higher mean arterial pressure as well as HR than the WT mice.…”

Section: Discussionmentioning

confidence: 99%

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

Tsujikawa

Yayama

Hayashi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

122

132

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Calcitonin gene-related peptide (CGRP) is thought to be a prominent neuropeptide in cardiovascular regulation and neuroimmune modulation. There are two isoforms of CGRP (␣CGRP and ␤CGRP), 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. ␣CGRP was found to have a potent vascular relaxant activity compared with ␤CGRP 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. ␣CGRP and ␤CGRP equally suppressed the production of TNF-␣ 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.gene-disrupted mice ͉ calcitonin gene-related peptide ͉ adrenomedullin ͉ neuropeptide ͉ dendritic cells C alcitonin gene-related peptide (CGRP) is a 37-aa neuropeptide that is produced in the neural body of dorsal root ganglion cells and released from sensory nerve endings. There are two isoforms of CGRP: ␣ and ␤ in rats and mice and I and II in humans. These differ in their peptide sequences by 1 aa (rats) and 3 aa (mice and humans) of the 37 aa (1). ␣CGRP is produced mainly in the nervous system by the tissue-specific alternative splicing of the primary RNA transcript of the calcitonin/CGRP gene. On the other hand, ␤CGRP is produced not only in the neuronal tissues but also in the enteric nerves of the intestine (2) and in immune cells such as T cells (3). Pharmacologically, ␣CGRP is known to have the most potent vasodilatory activity (4). Most blood vessels are surrounded by a dense perivascular CGRPergic neural network, suggesting the physiological importance of CGRP in vasodilatory regulation (5). ␣CGRP also contributes to local neurogenic inflammation and nociception (6). Moreover, the functions of immune cells such as macrophages (7,8), Langerhans cells (8), and T cells (9, 10) are modulated by ␣CGRP. However, the precise functional differences between ␣CGRP and ␤CGRP remain unclear.Historically, CGRP receptors have been classified into two classes: CGRP 1 and CGRP 2 receptors. The CGRP 1 receptors are m...

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“…We generated CGRP knockout mice using a targeting DNA construct that replaced exon 5 encoding a CGRP-specific region [25]. C57BL/6 pure background mice were used for bone marrow transplantation (BMT) experiments.…”

Section: Animalsmentioning

confidence: 99%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene.Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule.We compared the effect of CGRP deficiency on neointima formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointima formation after vascular injury was markedly enhanced in CGRP-/-mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointima formation in CGRP-/-mice. In vitro analysis showed CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.

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Elevated Sympathetic Nervous Activity in Mice Deficient in αCGRP

Cited by 149 publications

References 25 publications

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

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

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

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