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Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based view involving extracellular matrix (ECM) architecture, transforming growth factor-\u03b2 (TGF\u03b2) signaling, and vascular smooth muscle cell contractility. Marfan syndrome, Loeys\u2013Dietz syndrome, and nonsyndromic HTAD demonstrate how genetic mutations can disrupt the components that stabilize the aortic wall. These pathogenic mechanisms influence matrix organization, intracellular signaling, and the contractile machinery within the mechanically stressed proximal aorta. In this review, we summarize current mechanistic insights into the major forms of HTAD and discuss how new molecular and cellular concepts could influence surveillance, genetic counseling, and genotype-guided therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cells15100936","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"936","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structural and Signaling Mechanisms of Aortic Wall Failure in Heritable Thoracic Aortic Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-3347","authenticated-orcid":false,"given":"Norifumi","family":"Takeda","sequence":"first","affiliation":[{"name":"The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Tokyo 113-8655, Japan"},{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6615-6196","authenticated-orcid":false,"given":"Hiroki","family":"Yagi","sequence":"additional","affiliation":[{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Tokyo 113-8655, Japan"},{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8719-3997","authenticated-orcid":false,"given":"Takayuki","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo 113-8655, Japan"},{"name":"Department of Computational Diagnostic Radiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5341-7241","authenticated-orcid":false,"given":"Hitomi","family":"Aono-Setoguchi","sequence":"additional","affiliation":[{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Tokyo 113-8655, Japan"},{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Inuzuka","sequence":"additional","affiliation":[{"name":"Marfan Syndrome Center, The University of Tokyo Hospital, Tokyo 113-8655, Japan"},{"name":"Department of Pediatrics, The University of Tokyo Hospital, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issei","family":"Komuro","sequence":"additional","affiliation":[{"name":"Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"},{"name":"International University of Health and Welfare, Tokyo 107-8402, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Marcos-Rios, D., Rochano-Ortiz, A., San Sebastian-Jaraba, I., Fernandez-Gomez, M.J., Mendez-Barbero, N., and Oller, J. 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