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Many alarmins have been found to increase vascular tone and oppose endothelium\u2010dependent dilatation (EDD). Interleukin (IL)\u201033 plays a prominent role in lung injury and can be released during vascular injury and in chronic studies found to be cardioprotective. Our recent work has implicated IL\u201033 in acute vascular dysfunction following inhalation of engineered nanomaterials (ENM). However, the mechanisms linking IL\u201033 to vascular tone have not been interrogated. We therefore aimed to determine whether IL\u201033 directly influenced microvascular tone and endothelial function. Isolated feed arteries and <jats:italic>in vivo<\/jats:italic> arterioles from male and female Sprague\u2013Dawley rats were used to determine direct vascular actions of IL\u201033. Mesenteric feed arteries and arterioles demonstrated reduced intraluminal diameters when treated with increasing concentrations of recombinant IL\u201033. IL\u201033 activated extracellular signal regulated kinase (ERK)1\/2 of rat aortic smooth muscle cells but not phosphorylation of myosin light chain kinase. This suggested IL\u201033\u00a0may sensitize arterioles to Ca<jats:sup>2+<\/jats:sup>\u2010mediated responses. Indeed, IL\u201033 augmented the myogenic\u2010 and phenylephrine\u2010induced vasoconstriction. Additionally, incubation of arterioles with 1\u00a0ng IL\u201033 attenuated ACh\u2010mediated EDD. Mechanistically, in human aortic endothelial cells, we demonstrate that IL\u201033\u2010mediated ERK1\/2 activation leads to inhibitory phosphorylation of serine 602 on endothelial nitric oxide synthase. Finally, we demonstrate that IL\u201033\u2010ERK1\/2 contributes to vascular tone following two known inducers of IL\u201033; ENM inhalation and the rupture endothelial cells. The present study provides novel evidence that IL\u201033 increases vascular tone via canonical ERK1\/2 activation in microvascular smooth muscle and endothelium. Altogether, it is suggested IL\u201033 plays a critical role in microvascular homeostasis following barrier cell injury.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16386-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Interleukin (IL)\u201033 causes a concentration\u2010dependent reduction in feed artery diameter.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>IL\u201033 acts on vascular smooth muscle cells to augment Ca<jats:sup>2+<\/jats:sup>\u2010mediated processes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>IL\u201033 causes inhibitory phosphorylation of endothelial nitric oxide synthase and opposes endothelium\u2010dependent dilatation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Engineered nanomaterial\u2010induced lung injury and endothelial cell rupture in part act through IL\u201033 to mediate increased vascular tone.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286990","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T14:44:47Z","timestamp":1731595487000},"page":"6087-6107","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The alarmin, interleukin\u201033, increases vascular tone via extracellular signal regulated kinase\u2010mediated Ca<sup>2+<\/sup> sensitization and endothelial nitric oxide synthase inhibition"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0173-3188","authenticated-orcid":false,"given":"Evan","family":"DeVallance","sequence":"first","affiliation":[{"name":"Department of Physiology, Pharmacology &amp; Toxicology, Health Sciences Center West Virginia University  Morgantown WV USA"},{"name":"Center for Inhalation Toxicology West Virginia University School of Medicine  Morgantown WV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Bowdridge","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology &amp; Toxicology, Health Sciences Center West Virginia University  Morgantown WV USA"},{"name":"Center for Inhalation Toxicology West Virginia University School of Medicine  Morgantown WV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"Garner","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology &amp; Toxicology, Health Sciences Center West Virginia University  Morgantown WV USA"},{"name":"Center for Inhalation Toxicology West Virginia University School of Medicine  Morgantown WV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Griffith","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology &amp; Toxicology, Health Sciences Center West Virginia University  Morgantown WV USA"},{"name":"Center for Inhalation Toxicology West Virginia University School of Medicine  Morgantown WV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Seman","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology &amp; Toxicology, Health Sciences Center West Virginia University  Morgantown WV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Batchelor","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology &amp; Toxicology, Health Sciences Center West Virginia University  Morgantown WV USA"},{"name":"Center for Inhalation Toxicology West Virginia University School of Medicine  Morgantown WV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9751-538X","authenticated-orcid":false,"given":"Murugesan","family":"Velayutham","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Health Sciences Center West Virginia University  Morgantown WV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6983-0200","authenticated-orcid":false,"given":"W. 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