{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T01:51:06Z","timestamp":1786499466880,"version":"build-2736575974"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T00:00:00Z","timestamp":1728518400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T00:00:00Z","timestamp":1728518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"crossref","award":["Vici grant 09150181910040"],"award-info":[{"award-number":["Vici grant 09150181910040"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"crossref","award":["Vici grant 09150181910040"],"award-info":[{"award-number":["Vici grant 09150181910040"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Headache Pain"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Different responses in human coronary arteries (HCA) and human middle meningeal arteries (HMMA) were observed for some of the novel CGRP receptor antagonists, the gepants, for inhibiting CGRP-induced relaxation. These differences could be explained by the presence of different receptor populations in the two vascular beds. Here, we aim to elucidate which receptors are involved in the relaxation to calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) in HCA and HMMA.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>RNA was isolated from homogenized human arteries (23 HCAs; 12\u00a0F, 11\u00a0M, age 50\u2009\u00b1\u20093 years and 26 HMMAs; 14\u00a0F, 12\u00a0M, age 51\u2009\u00b1\u20093 years) and qPCR was performed for different receptor subunits. Additionally, relaxation responses to CGRP, AM or AM2 of the human arteries were quantified using a Mulvany myograph system, in the presence or absence of the adrenomedullin 1 receptor antagonist AM<jats:sub>22-52<\/jats:sub> and\/or olcegepant.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Calcitonin-like receptor (CLR) mRNA was expressed equally in both vascular beds, while calcitonin receptor (CTR) and receptor activity-modifying protein 3 (RAMP3) expression was low and could not be detected in all samples. RAMP1 expression was similar in HCA and HMMA, while RAMP2 expression was higher in HMMA. Moreover, receptor component protein (RCP) expression was higher in HMMA than in HCA. Functional experiments showed that olcegepant inhibits relaxation to all three agonists in both vascular beds. In HCA, antagonist AM<jats:sub>22-52<\/jats:sub> did not inhibit relaxation to any of the agonists, while a trend for blocking relaxation to AM and AM2 could be observed in HMMA.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Based on the combined results from receptor subunit mRNA expression and the functional responses in both vascular tissues, relaxation of HCA is mainly mediated via the canonical CGRP receptor (CLR-RAMP1), while relaxation of HMMA can be mediated via both the canonical CGRP receptor and the adrenomedullin 1 receptor (CLR-RAMP2). Future research should investigate whether RAMP2 predominance over RAMP1 in the meningeal vasculature results in altered migraine susceptibility or in a different response to anti-migraine medication in these patients. Moreover, the exact role of RCP in CGRP receptor signalling should be elucidated in future research.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10194-024-01863-7","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T08:02:03Z","timestamp":1728547323000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications"],"prefix":"10.1186","volume":"25","author":[{"given":"Tessa","family":"de Vries","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Schutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoon","family":"van den Bogaerdt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Dammers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. H. Jan","family":"Danser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoinette","family":"MaassenVanDenBrink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,10]]},"reference":[{"issue":"10","key":"1863_CR1","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1177\/0333102410368444","volume":"30","author":"JM Hansen","year":"2010","unstructured":"Hansen JM et al (2010) Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30(10):1179\u20131186","journal-title":"Cephalalgia"},{"issue":"1","key":"1863_CR2","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1046\/j.1468-2982.2002.00310.x","volume":"22","author":"LH Lassen","year":"2002","unstructured":"Lassen LH et al (2002) CGRP may play a causative role in migraine. Cephalalgia 22(1):54\u201361","journal-title":"Cephalalgia"},{"issue":"2","key":"1863_CR3","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1002\/ana.410280213","volume":"28","author":"PJ Goadsby","year":"1990","unstructured":"Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183\u2013187","journal-title":"Ann Neurol"},{"issue":"1","key":"1863_CR4","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1002\/ana.410330109","volume":"33","author":"PJ Goadsby","year":"1993","unstructured":"Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33(1):48\u201356","journal-title":"Ann Neurol"},{"issue":"4","key":"1863_CR5","doi-asserted-by":"publisher","first-page":"333102423115936","DOI":"10.1177\/03331024231159366","volume":"43","author":"F Haghdoost","year":"2023","unstructured":"Haghdoost F et al (2023) Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: a systematic review and network meta-analysis of phase 3 randomised controlled trials. Cephalalgia 43(4):3331024231159366","journal-title":"Cephalalgia"},{"key":"1863_CR6","doi-asserted-by":"crossref","unstructured":"Moreno-Ajona D, Villar-Mart\u00ednez MD, Goadsby PJ (2022) New Generation gepants: Migraine Acute and Preventive medications. J Clin Med, 11(6)","DOI":"10.3390\/jcm11061656"},{"issue":"1","key":"1863_CR7","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bph.14075","volume":"175","author":"DL Hay","year":"2018","unstructured":"Hay DL et al (2018) Update on the pharmacology of calcitonin\/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol 175(1):3\u201317","journal-title":"Br J Pharmacol"},{"issue":"5","key":"1863_CR8","doi-asserted-by":"publisher","first-page":"407","DOI":"10.2174\/13892037113149990057","volume":"14","author":"IM Dickerson","year":"2013","unstructured":"Dickerson IM (2013) Role of CGRP-receptor component protein (RCP) in CLR\/RAMP function. Curr Protein Pept Sci 14(5):407\u2013415","journal-title":"Curr Protein Pept Sci"},{"issue":"8","key":"1863_CR9","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.3390\/ph16081075","volume":"16","author":"T de Vries","year":"2023","unstructured":"de Vries T et al (2023) Blocking the CGRP receptor: differences across human vascular beds. Pharmaceuticals 16(8):1075\u20131085","journal-title":"Pharmaceuticals"},{"issue":"1\u20133","key":"1863_CR10","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.ejphar.2005.12.039","volume":"531","author":"W Chai","year":"2006","unstructured":"Chai W et al (2006) The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts. Eur J Pharmacol 531(1\u20133):246\u2013253","journal-title":"Eur J Pharmacol"},{"key":"1863_CR11","doi-asserted-by":"publisher","first-page":"1184766","DOI":"10.3389\/fnins.2023.1184766","volume":"17","author":"J Xiong","year":"2023","unstructured":"Xiong J et al (2023) Calcitonin gene-related peptide: a potential protective agent in cerebral ischemia-reperfusion injury. Front Neurosci 17:1184766","journal-title":"Front Neurosci"},{"issue":"9","key":"1863_CR12","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.tips.2016.06.002","volume":"37","author":"A MaassenVanDenBrink","year":"2016","unstructured":"MaassenVanDenBrink A et al (2016) Wiping out CGRP: potential Cardiovascular risks. Trends Pharmacol Sci 37(9):779\u2013788","journal-title":"Trends Pharmacol Sci"},{"issue":"4","key":"1863_CR13","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1002\/ana.25831","volume":"88","author":"IA Mulder","year":"2020","unstructured":"Mulder IA et al (2020) Anti-migraine calcitonin gene-related peptide receptor antagonists worsen cerebral ischemic outcome in mice. Ann Neurol 88(4):771\u2013784","journal-title":"Ann Neurol"},{"issue":"4","key":"1863_CR14","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1177\/0333102419884943","volume":"40","author":"E Rubio-Beltr\u00e1n","year":"2019","unstructured":"Rubio-Beltr\u00e1n E et al (2019) Characterisation of the calcitonin gene-related peptide receptor antagonists ubrogepant and atogepant in human isolated coronary, cerebral and middle meningeal arteries. Cephalalgia 40(4):357\u2013366","journal-title":"Cephalalgia"},{"issue":"1","key":"1863_CR15","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1161\/01.RES.41.1.19","volume":"41","author":"MJ Mulvany","year":"1977","unstructured":"Mulvany MJ, Halpern W (1977) Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 41(1):19\u201326","journal-title":"Circ Res"},{"key":"1863_CR16","unstructured":"The Human Protein Atlas, Smooth Muscle Tissue Normalized Expression. Accessed (2024) Version 23.0, 19-06-2023: https:\/\/www.proteinatlas.org\/"},{"issue":"1","key":"1863_CR17","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1124\/jpet.102.037754","volume":"304","author":"P Hasbak","year":"2003","unstructured":"Hasbak P et al (2003) Investigation of CGRP receptors and peptide pharmacology in human coronary arteries. Characterization with a nonpeptide antagonist. J Pharmacol Exp Ther 304(1):326\u2013333","journal-title":"J Pharmacol Exp Ther"},{"issue":"8","key":"1863_CR18","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1038\/sj.bjp.0704210","volume":"133","author":"P Hasbak","year":"2001","unstructured":"Hasbak P et al (2001) CGRP receptors mediating CGRP-, adrenomedullin- and amylin-induced relaxation in porcine coronary arteries. Characterization with \u2018Compound 1\u2019 (WO98\/11128), a non-peptide antagonist. Br J Pharmacol 133(8):1405\u20131413","journal-title":"Br J Pharmacol"},{"issue":"2\u20133","key":"1863_CR19","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.ejphar.2003.09.021","volume":"481","author":"I Jansen-Olesen","year":"2003","unstructured":"Jansen-Olesen I et al (2003) In-depth characterization of CGRP receptors in human intracranial arteries. Eur J Pharmacol 481(2\u20133):207\u2013216","journal-title":"Eur J Pharmacol"},{"issue":"1","key":"1863_CR20","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s10194-024-01744-z","volume":"25","author":"TA Rees","year":"2024","unstructured":"Rees TA et al (2024) Calcitonin receptor, calcitonin gene-related peptide and amylin distribution in C1\/2 dorsal root ganglia. J Headache Pain 25(1):36","journal-title":"J Headache Pain"},{"key":"1863_CR21","doi-asserted-by":"publisher","first-page":"860037","DOI":"10.3389\/fphys.2022.860037","volume":"13","author":"TA Rees","year":"2022","unstructured":"Rees TA et al (2022) CGRP and the calcitonin receptor are co-expressed in mouse, rat and human trigeminal ganglia neurons. Front Physiol 13:860037","journal-title":"Front Physiol"},{"issue":"3","key":"1863_CR22","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/sj.bjp.0705472","volume":"140","author":"DL Hay","year":"2003","unstructured":"Hay DL et al (2003) CL\/RAMP2 and CL\/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS. Br J Pharmacol 140(3):477\u2013486","journal-title":"Br J Pharmacol"},{"issue":"6","key":"1863_CR23","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1016\/j.celrep.2020.01.029","volume":"30","author":"F Garces","year":"2020","unstructured":"Garces F et al (2020) Molecular Insight into Recognition of the CGRPR Complex by Migraine Prevention Therapy Aimovig (Erenumab). Cell Rep 30(6):1714\u20131723","journal-title":"Cell Rep"},{"issue":"9","key":"1863_CR24","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/j.str.2010.05.014","volume":"18","author":"E ter Haar","year":"2010","unstructured":"ter Haar E et al (2010) Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure 18(9):1083\u20131093","journal-title":"Structure"},{"issue":"1","key":"1863_CR25","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/sj.bjp.0704844","volume":"137","author":"DL Hay","year":"2002","unstructured":"Hay DL et al (2002) A comparison of the actions of BIBN4096BS and CGRP(8\u201337) on CGRP and adrenomedullin receptors expressed on SK-N-MC, L6, col 29 and rat 2 cells. Br J Pharmacol 137(1):80\u201386","journal-title":"Br J Pharmacol"},{"issue":"1","key":"1863_CR26","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1111\/j.1476-5381.2011.01633.x","volume":"166","author":"EL Moore","year":"2012","unstructured":"Moore EL, Salvatore CA (2012) Targeting a family B GPCR\/RAMP receptor complex: CGRP receptor antagonists and migraine. Br J Pharmacol 166(1):66\u201378","journal-title":"Br J Pharmacol"},{"key":"1863_CR27","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.3389\/fphar.2020.01240","volume":"11","author":"KS Pan","year":"2020","unstructured":"Pan KS et al (2020) Antagonism of CGRP Signaling by Rimegepant at two receptors. Front Pharmacol 11:1240","journal-title":"Front Pharmacol"},{"issue":"0","key":"1863_CR28","first-page":"1","volume":"0","author":"M Bhakta","year":"2021","unstructured":"Bhakta M et al (2021) Migraine therapeutics differentially modulate the CGRP pathway. Cephalalgia 0(0):1\u201316","journal-title":"Cephalalgia"},{"issue":"11","key":"1863_CR29","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1177\/0333102419851810","volume":"39","author":"KA Haanes","year":"2019","unstructured":"Haanes KA et al (2019) Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models. Cephalalgia 39(11):1421\u20131434","journal-title":"Cephalalgia"},{"issue":"11","key":"1863_CR30","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1016\/S0196-9781(01)00517-4","volume":"22","author":"MA Prado","year":"2001","unstructured":"Prado MA et al (2001) The role of the CGRP-receptor component protein (RCP) in adrenomedullin receptor signal transduction. Peptides 22(11):1773\u20131781","journal-title":"Peptides"},{"issue":"40","key":"1863_CR31","doi-asserted-by":"publisher","first-page":"31438","DOI":"10.1074\/jbc.M005604200","volume":"275","author":"BN Evans","year":"2000","unstructured":"Evans BN et al (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 275(40):31438\u201331443","journal-title":"J Biol Chem"},{"issue":"10","key":"1863_CR32","doi-asserted-by":"publisher","first-page":"4207","DOI":"10.1210\/endo.138.10.5447","volume":"138","author":"M Naghashpour","year":"1997","unstructured":"Naghashpour M et al (1997) Inhibitory effect of calcitonin gene-related peptide on myometrial contractility is diminished at parturition. Endocrinology 138(10):4207\u20134214","journal-title":"Endocrinology"}],"container-title":["The Journal of Headache and Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10194-024-01863-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10194-024-01863-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10194-024-01863-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T20:22:16Z","timestamp":1728591736000},"score":1,"resource":{"primary":{"URL":"https:\/\/thejournalofheadacheandpain.biomedcentral.com\/articles\/10.1186\/s10194-024-01863-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,10]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1863"],"URL":"https:\/\/doi.org\/10.1186\/s10194-024-01863-7","relation":{},"ISSN":["1129-2377"],"issn-type":[{"value":"1129-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,10]]},"assertion":[{"value":"18 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"TdV, DS, AvdB, AV, RD and AHJD declare no conflicts of interest. AMvdB received personal fees (fees as advisor or speaker, consultancy, any other) from Allergan-Abbvie, Lilly, Novartis and Teva. She received research support from Novartis, Satsuma and Tonix, as well as independent research support from the Dutch Research Council and the Netherlands Organisation for Health Research and Development.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"176"}}