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

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.