Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications.
Humans
Meningeal Arteries
/ drug effects
Middle Aged
Male
Female
Adrenomedullin
/ metabolism
Receptors, Calcitonin Gene-Related Peptide
/ metabolism
Coronary Vessels
/ drug effects
Calcitonin Receptor-Like Protein
/ metabolism
Receptor Activity-Modifying Protein 1
/ metabolism
Calcitonin Gene-Related Peptide
/ metabolism
Receptor Activity-Modifying Protein 3
/ metabolism
Receptor Activity-Modifying Protein 2
/ metabolism
Vasodilation
/ drug effects
Calcitonin Gene-Related Peptide Receptor Antagonists
/ pharmacology
Peptide Hormones
AM22-52
Adrenomedullin
CGRP
Human arteries
Olcegepant
Receptor expression
Vasodilation
qPCR
Journal
The journal of headache and pain
ISSN: 1129-2377
Titre abrégé: J Headache Pain
Pays: England
ID NLM: 100940562
Informations de publication
Date de publication:
10 Oct 2024
10 Oct 2024
Historique:
received:
18
07
2024
accepted:
08
09
2024
medline:
11
10
2024
pubmed:
11
10
2024
entrez:
10
10
2024
Statut:
epublish
Résumé
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. 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 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 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSION
CONCLUSIONS
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.
Identifiants
pubmed: 39390360
doi: 10.1186/s10194-024-01863-7
pii: 10.1186/s10194-024-01863-7
doi:
Substances chimiques
Adrenomedullin
148498-78-6
Receptors, Calcitonin Gene-Related Peptide
0
Calcitonin Receptor-Like Protein
0
Receptor Activity-Modifying Protein 1
0
Calcitonin Gene-Related Peptide
JHB2QIZ69Z
RAMP2 protein, human
0
ADM2 protein, human
0
Receptor Activity-Modifying Protein 3
0
RAMP1 protein, human
0
Receptor Activity-Modifying Protein 2
0
RAMP3 protein, human
0
Calcitonin Gene-Related Peptide Receptor Antagonists
0
CALCRL protein, human
0
Peptide Hormones
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
176Subventions
Organisme : Dutch Research Council
ID : Vici grant 09150181910040
Pays : Netherlands
Organisme : Dutch Research Council
ID : Vici grant 09150181910040
Pays : Netherlands
Informations de copyright
© 2024. The Author(s).
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