Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications

• Published in: Journal of headache and pain 2024-10, Vol.25 (1), p.176-8, Article 176
• Main Authors: de Vries, Tessa, Schutter, Dennis, van den Bogaerdt, Antoon, Vincent, Arnaud, Dammers, Ruben, Danser, A. H. Jan, MaassenVanDenBrink, Antoinette
• Format: Article
• Language: English
• Subjects: Adrenomedullin; Adrenomedullin - genetics; Adrenomedullin - metabolism; Adrenomedullin - pharmacology; Agonists; AM22-52; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - metabolism; Calcitonin Gene-Related Peptide Receptor Antagonists - pharmacology; Calcitonin Receptor-Like Protein - genetics; Calcitonin Receptor-Like Protein - metabolism; CGRP; Coronary artery; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Female; Gene expression; Headache; Human arteries; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Meningeal Arteries - drug effects; Meningeal Arteries - metabolism; Middle Aged; Migraine; Neurology; Olcegepant; Pain Medicine; Peptide Hormones; qPCR; Receptor activity modifying proteins; Receptor Activity-Modifying Protein 1 - genetics; Receptor Activity-Modifying Protein 1 - metabolism; Receptor Activity-Modifying Protein 2 - genetics; Receptor Activity-Modifying Protein 2 - metabolism; Receptor Activity-Modifying Protein 3 - genetics; Receptor Activity-Modifying Protein 3 - metabolism; Receptors, Calcitonin Gene-Related Peptide - metabolism; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 1129-2377; 1129-2369; 1129-2377
• DOI: 10.1186/s10194-024-01863-7

Background 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. Methods RNA was isolated from homogenized human arteries (23 HCAs; 12 F, 11 M, age 50 ± 3 years and 26 HMMAs; 14 F, 12 M, age 51 ± 3 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 22-52 and/or olcegepant. Results 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 22-52 did not inhibit relaxation to any of the agonists, while a trend for blocking relaxation to AM and AM2 could be observed in HMMA. Conclusion 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.