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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>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\u2010030031 (TRPA1), isosakuranetin (TRPM3), capsazepine (TRPV1), olcegepant (calcitonin gene\u2010related peptide [CGRP] receptor), L\u2010NAME (nitric oxide synthase [NOS]), indomethacin (cyclooxygenase [COX]), TRAM\u201034\u2009+\u2009apamin (K<jats:sup>+<\/jats:sup> channels) or MK\u2010801 (<jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate [NMDA] receptor). Fluorescence microscopy, quantitative polymerase chain reaction (qPCR), and western blotting were performed to investigate their location and expression, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In HCAs and HMMAs, (i) capsaicin\u2010induced relaxation remained unchanged after the above\u2010mentioned antagonists\/blockers\/inhibitors and (ii) cinnamaldehyde\u2010induced relaxation was blocked by olcegepant. PregS\u2010induced maximal relaxation was significantly enhanced in isolated arteries from females compared with males and was inhibited after isosakuranetin, MK\u2010801 or L\u2010NAME. TRPM3 mRNA and protein expression, along with NMDA protein levels, were higher in arteries from females than males.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Modulation of vascular tone in HCAs and HMMAs by activation of TRPM3 is sex\u2010dependent, likely involving NMDA receptors. This represents a new therapeutic direction, targeting sex dimorphism in migraine and its related cardiovascular events.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17472","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T01:45:56Z","timestamp":1739756756000},"page":"2503-2523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Sex differences in the vasoactive effect of transient receptor potential channels: TRPM3 as a new therapeutic target for (neuro)vascular disorders"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4559-4028","authenticated-orcid":false,"given":"Eduardo","family":"Rivera\u2010Mancilla","sequence":"first","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Usha M.","family":"Musterd\u2010Bhaggoe","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis","family":"Schutter","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoon","family":"van den Bogaerdt","sequence":"additional","affiliation":[{"name":"Heart Valve Department ETB\u2010BISLIFE  Beverwijk The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnaud J. P. E.","family":"Vincent","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4117-1343","authenticated-orcid":false,"given":"Carlos M.","family":"Villal\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Pharmacobiology Cinvestav\u2010Coapa  Mexico City Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-3585","authenticated-orcid":false,"given":"Alexander H. 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