Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.

1056α -Calcitonin gene-related peptide (αCGRP) is a potent vasodilator 1 and a hypotensive peptide. It is primarily localized to the sensory nervous system, with a perivascular innervation and considered to be the major cardiovascular form, as compared with the structurally similar βCGRP. CGRP acts via a G-protein-coupled receptor (calcitonin-like receptor) when dimerized with a single transmembrane-spanning receptor activity-modifying protein RAMP1 2 signaling via cAMP and other pathways. 3,4 CGRP does not play a primary role in the regulation of basal blood pressure (BP) in normal individuals 5,6 but is suggested to have protective properties, in cardiovascular disease, 7,8 including attenuation of vascular smooth muscle proliferation, 9 hyperplasia, 10,11 and stimulation of endothelial cell proliferation 12 and endothelial progenitor cells. 13 Evidence indicates the importance of CGRP in aggressive models of rodent hypertension that are centered on the kidney. 14,15 By comparison, there is little evidence of detailed analysis involving the ongoing influence of endogenous CGRP on hypertensive mechanisms and vascular remodeling, especially with regard to NO and oxidative stress pathways.Sensory nerve-derived CGRP release is stimulated by mechanisms that include angiotensin II (AngII) and sympathetic nerve reflexes, 3,4 baroreflex sensitivity, 16 and sensory nerve activators. 17,18 We have investigated the AngII hypertension model in wild-type (WT) and αCGRP knockout (αCGRPKO) mice that have similar resting BP. We hypothesized that αCGRP is protective against the onset and development of hypertension, and the aim was to identify mechanisms by which αCGRP is protective in this model. The novel findings show Abstract-α-Calcitonin gene-related peptide (αCGRP) is a vasodilator, but there is limited knowledge of its long-term cardiovascular protective influence. We hypothesized that αCGRP protects against the onset and development of angiotensin II-induced hypertension and have identified protective mechanisms at the vascular level. Wild-type and αCGRP knockout mice that have similar baseline blood pressure were investigated in the angiotensin II hypertension model for 14 and 28 days. αCGRP knockout mice exhibited enhanced hypertension and aortic hypertrophy. αCGRP gene expression was increased in dorsal root ganglia and at the conduit and resistance vessel level of wild-type mice at both time points. βCGRP gene expression was also observed and shown to be linked to plasma levels of CGRP. Mesenteric artery contractile and relaxant responses in vitro and endothelial NO synthase expression were similar in all groups. The aorta exhibited vascular hypertrophy, increased collagen formation, and oxidant stress markers in response to angiotensin II, with highest effects observed in αCGRP knockout mice. Gene and protein expression of endothelial NO synthase was lacking in the aortae after angiotensin II treatment, especially in αCGRP knockout mice. These results demonstrate the ongoing upregulation of αCGRP at the levels...

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Pressor responses to both angiotensin II (Ang II) and noradrenaline (NA) were reduced in 20-day-pregnant rats compared with those in non-pregnant animals, regardless of whether the results were expressed in terms of the dose per kilogram of body weight or per millilitre of estimated plasma volume. Inhibition of prostaglandin production with indomethacin (10 mg kg-1, i.v.) was not accompanied by any significant effect on responses to Ang II in either non-pregnant or 20-day-pregnant animals. However, it attenuated the effects of NA in 20-day-pregnant rats. Indomethacin (10(-5) or 3 x 10(-5) M) did not potentiate in vitro vasoconstrictor responses to phenylephrine of endothelium-intact or -denuded thoracic aortic rings from non-pregnant or 20-day-pregnant rats. These results suggest that subsensitivity to Ang II or NA during pregnancy in the rat is not due to dilution of the dose of these autacoids resulting from increased plasma volume, nor to an increased output of vasodilator prostaglandins.

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Calcitonin gene-related peptide (CGRP) is a potent microvascular vasodilator derived predominantly from perivascular sensory neurones. It has been suggested that vascular reactivity to CGRP is diminished with increasing age whilst levels of CGRP are also thought to decline. Our aim was to investigate how vascular responses to CGRP changed with age in α-CGRP wild type (WT) and knockout (KO) mice. Male and female α-CGRP WT and KO mice were aged to 15 months at which point mice were killed and second order mesenteric arteries were mounted in a wire myograph. Aortic tissue was collected and mRNA expression of CGRP receptor subunits was evaluated by RTqPCR. Data were analysed by ANOVA and Student's t test, where appropriate.Maximal relaxation to CGRP (100 nM) in aged WT mice produced a 75.30±7.48% relaxation from initial tone induced by 10 nM U46619. Conversely, maximal relaxation to CGRP in aged KO vessels produced a 31.33±8.74% decline in tone, an effect found to be significantly different ( p<0.01). Analysis of gene expression of CGRP receptor subunits (calcitonin receptor-like receptor, receptor activity modifying protein 1 and receptor component protein) found a general trend towards an increase in expression within the aortic wall. This study has shown that whilst vascular reactivity to CGRP is diminished with advancing age, it does not appear to be as a result of decreased receptor expression.This project is funded by The British Heart Foundation.