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The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF\u2010\u03b2\u2010driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF\u2010\u03b2\u2010dependent and opposed by ERK in vitro<jats:italic>,<\/jats:italic> implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling <jats:italic>via<\/jats:italic> Notch3 in MFS<jats:italic>.<\/jats:italic> Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF\u2010\u03b2\u2010dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a \u2018mixed\u2019 contractile\u2010synthetic phenotype in MFS aortic aneurysm;\u00a0and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.<\/jats:p>","DOI":"10.1111\/jcmm.14921","type":"journal-article","created":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T13:11:57Z","timestamp":1577711517000},"page":"2369-2383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Divergent effects of canonical and non\u2010canonical TGF\u2010\u03b2 signalling on mixed contractile\u2010synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root 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