{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:18:33Z","timestamp":1783570713421,"version":"3.55.0"},"reference-count":122,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017628","name":"Ines-Mandl Research Foundation","doi-asserted-by":"crossref","award":["2025 IMRF grant"],"award-info":[{"award-number":["2025 IMRF grant"]}],"id":[{"id":"10.13039\/100017628","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-\u03b2, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian\/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type\u2013specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies.<\/jats:p>","DOI":"10.3390\/genes17070770","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanotransduction in Marfan Syndrome and Related Aortic Disorders: Insights from Transcriptomic Analyses"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5818-0900","authenticated-orcid":false,"given":"Anna","family":"Cantalupo","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6192-9970","authenticated-orcid":false,"given":"Jason R.","family":"Cook","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1101-2641","authenticated-orcid":false,"given":"Samia","family":"Lasaad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1744-1748","authenticated-orcid":false,"given":"Lisa M.","family":"Satlin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7814-0180","authenticated-orcid":false,"given":"Ravi","family":"Iyengar","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev.genom.8.080706.092303","article-title":"Genetic basis of thoracic aortic aneurysms and dissections: Focus on smooth muscle cell contractile dysfunction","volume":"9","author":"Milewicz","year":"2008","journal-title":"Annu. 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