Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
Heart Valve Department, ETB-BISLIFE, Beverwijk, The Netherlands.
J Headache Pain. 2024 Oct 10;25(1):176. doi: 10.1186/s10194-024-01863-7.
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 and/or olcegepant.
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 did not inhibit relaxation to any of the agonists, while a trend for blocking relaxation to AM and AM2 could be observed in HMMA.
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.
在一些新型降钙素基因相关肽（CGRP）受体拮抗剂—— gepants 中，观察到它们在抑制 CGRP 诱导的舒张方面在人冠状动脉（HCA）和人脑膜中动脉（HMMA）中表现出不同的反应。这些差异可以通过两种血管床中存在不同的受体群体来解释。在这里，我们旨在阐明哪些受体参与了 HCA 和 HMMA 中降钙素基因相关肽（CGRP）、肾上腺髓质素（AM）和肾上腺髓质素 2（AM2）的舒张反应。
从匀浆的人动脉（23 例 HCA；12 例女性，11 例男性，年龄 50±3 岁和 26 例 HMMA；14 例女性，12 例男性，年龄 51±3 岁）中分离 RNA，并进行 qPCR 以检测不同的受体亚基。此外，使用 Mulvany 肌描记系统定量测定人动脉对 CGRP、AM 或 AM2 的舒张反应，并在存在或不存在肾上腺髓质素 1 受体拮抗剂 AM 和/或 olcegepant 的情况下进行。
降钙素样受体（CLR）mRNA 在两种血管床中表达水平相等，而降钙素受体（CTR）和受体活性修饰蛋白 3（RAMP3）的表达水平较低，在所有样本中均无法检测到。RAMP1 的表达在 HCA 和 HMMA 中相似，而 RAMP2 的表达在 HMMA 中更高。此外，受体成分蛋白（RCP）在 HMMA 中的表达高于 HCA。功能实验表明，olcegepant 抑制两种血管床中所有三种激动剂的舒张。在 HCA 中，拮抗剂 AM 不能抑制任何激动剂的舒张，而在 HMMA 中可以观察到 AM 和 AM2 舒张的趋势。
基于受体亚基 mRNA 表达的综合结果和两种血管组织的功能反应，HCA 的舒张主要通过经典的 CGRP 受体（CLR-RAMP1）介导，而 HMMA 的舒张可以通过经典的 CGRP 受体和肾上腺髓质素 1 受体（CLR-RAMP2）介导。未来的研究应调查脑膜血管中 RAMP2 对 RAMP1 的优势是否导致偏头痛易感性改变或这些患者对偏头痛药物治疗的反应不同。此外，在未来的研究中应阐明 RCP 在 CGRP 受体信号转导中的确切作用。
