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However, the mechanistic pathways governing pathological scar formation remain incompletely understood. Here, we demonstrate that ADAMTS1 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 1), significantly upregulated in endothelial cells (ECs) following MI, plays a pivotal role in regulating cardiac fibroblast activation through a novel mechanotransduction pathway involving integrin \u03b18 (ITG\u03b18). Using EC\u2010specific ADAMTS1 overexpression and knockout mice combined with cardiac fibroblast\u2010specific ITG\u03b18 deletion models, we found that ADAMTS1 overexpression exacerbates cardiac dysfunction and increases scar size, while ADAMTS1 deficiency provides cardioprotection. Mechanistically, ADAMTS1 modulates extracellular matrix stiffness through proteoglycan (PG) cleavage rather than direct protein interactions, which activates ITG\u03b18 mechanosensing specifically in cardiac fibroblasts. Among integrin family members tested, ITG\u03b18 shows selective responsiveness to ADAMTS1\u2010mediated mechanical cues, as confirmed by tunable\u2010stiffness hydrogel experiments and validated through comprehensive proteomic and functional analyses. ITG\u03b18 deficiency rescues ADAMTS1\u2010induced cardiac dysfunction and reduces pathological scar formation. These findings reveal a previously unrecognized ADAMTS1\u2010ITG\u03b18 mechanotransduction pathway, representing a promising therapeutic target for optimizing post\u2010infarction cardiac remodeling.<\/jats:p>","DOI":"10.1002\/advs.202504138","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T17:05:55Z","timestamp":1758992755000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Adamts1 Exacerbates Post\u2010Myocardial Infarction Scar Formation via Mechanosensing of Integrin \u03b18"],"prefix":"10.1002","volume":"12","author":[{"given":"Chun\u2010Yan","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan 430060 P. R. China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan 430060 P. R. China"},{"name":"TaiKang Center for Life and Medical Sciences Wuhan University  Wuhan 430071 P. R. 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