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  3. Sex differences in the vasoactive effect of transient receptor potential channels: TRPM3 as a new therapeutic target for (neuro)vascular disorders

Sex differences in the vasoactive effect of transient receptor potential channels: TRPM3 as a new therapeutic target for (neuro)vascular disorders

  • Br J Pharmacol. 2025 Feb 16. doi: 10.1111/bph.17472.
Eduardo Rivera-Mancilla 1,  Usha M Musterd-Bhaggoe 1,  Dennis Schutter 1,  Antoon van den Bogaerdt 2,  Arnaud J P E Vincent 3,  Carlos M Villalón 4,  Alexander H J Danser 1,  Antoinette MaassenVanDenBrink 1
Affiliations

Affiliations

  • 1 Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 2 Heart Valve Department, ETB-BISLIFE, Beverwijk, The Netherlands.
  • 3 Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 4 Department of Pharmacobiology, Cinvestav-Coapa, Mexico City, Mexico.
PMID: 39956579 DOI: 10.1111/bph.17472
Abstract

Background and purpose: Sex-dependent vascular effects of transient receptor potential (TRP) channels and sex dimorphism in migraine are not yet fully characterized. We investigated the differential vasoactive effects of TRP ankyrin 1 (TRPA1), TRP melastatin 3 (TRPM3) and TRP vanilloid 1 (TRPV1) channels, their pharmacological mechanism(s), and localization and expression in human isolated blood vessels.

Experimental approach: Agonist responses to cinnamaldehyde (TRPA1), pregnenolone sulfate (PregS, TRPM3) or capsaicin (TRPV1) were analysed using wire myography in segments of human coronary (HCAs) and middle meningeal (HMMAs) arteries from men and women. The mechanisms involved in these responses were investigated using the antagonists/blockers/inhibitors: HC-030031 (TRPA1), isosakuranetin (TRPM3), capsazepine (TRPV1), olcegepant (Calcitonin gene-related peptide [CGRP] receptor), L-NAME (nitric oxide synthase [NOS]), indomethacin (cyclooxygenase [COX]), TRAM-34 + apamin (K+ channels) or MK-801 (N-methyl-d-aspartate [NMDA] receptor). Fluorescence microscopy, quantitative polymerase chain reaction (qPCR), and western blotting were performed to investigate their location and expression, respectively.

Key results: In HCAs and HMMAs, (i) capsaicin-induced relaxation remained unchanged after the above-mentioned antagonists/blockers/inhibitors and (ii) cinnamaldehyde-induced relaxation was blocked by olcegepant. PregS-induced maximal relaxation was significantly enhanced in isolated arteries from females compared with males and was inhibited after isosakuranetin, MK-801 or L-NAME. TRPM3 mRNA and protein expression, along with NMDA protein levels, were higher in arteries from females than males.

Conclusion and implications: Modulation of vascular tone in HCAs and HMMAs by activation of TRPM3 is sex-dependent, likely involving NMDA receptors. This represents a new therapeutic direction, targeting sex dimorphism in migraine and its related cardiovascular events.

Keywords

CGRP; NMDA receptors; TRP channels; migraine; sex differences; vascular tone.

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