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Recent research suggests a potential link between early\u2010stage TAD and endothelial barrier dysfunction, although the underlying mechanisms remain unclear. Single\u2010cell RNA sequencing data from patients reveal that dysregulated Calpain\u20102 expression modulates endothelial focal adhesion proteins, serving as an early pathological hallmark and driver of TAD. Elevated plasma calpain activity is strongly associated with an increased risk of TAD and organ dysfunction. Both endogenous and exogenous calpain inhibitors effectively prevent TAD onset and progression in murine models induced by \u03b2\u2010aminopropionitrile (BAPN). In early TAD, endothelial junction integrity in the ascending aorta and aortic arch is compromised. Endothelial\u2010specific deletion of Capns1 mitigates early and sustained endothelial focal adhesion damage by reducing aberrant expression of Integrin alpha\u2010V(Itgav), vinculin, and talin\u20101, thereby decreasing TAD incidence. In contrast, macrophage\u2010specific Capns1 knockout does not impact TAD development but accelerates aortic dissection rupture in later stages. Mechanistically, angiotensin II upregulates Calpain\u20102, leading to endothelial focal adhesion activation through talin1 cleavage and Itgav assembly, thereby compromising endothelial integrity and permeability. These findings identify potential therapeutic targets for TAD prevention and treatment.<\/jats:p>","DOI":"10.1002\/advs.202501112","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T04:15:22Z","timestamp":1743740122000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Calpain\u20102\u2010Mediated Endothelial Focal Adhesion Disruption in Thoracic Aortic Dissection"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-2957","authenticated-orcid":false,"given":"Xiaomei","family":"Teng","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital of Soochow University  899 Pinghai Road Suzhou 215006 China"},{"name":"Institute for Cardiovascular Science Soochow University  178 Ganjiang Road Suzhou 215006 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