{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:00:55Z","timestamp":1792508455336,"version":"4.5.0"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2018,8,31]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              We used a mouse model of postnatal ascending aortic aneurysms (\n              <jats:italic>\n                Fbln4\n                <jats:sup>SMKO<\/jats:sup>\n              <\/jats:italic>\n              ; termed\n              <jats:italic>SMKO<\/jats:italic>\n              [SMC-specific knockout]), in which deletion of\n              <jats:italic>Fbln4<\/jats:italic>\n              (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulated in\n              <jats:italic>SMKO<\/jats:italic>\n              ascending aortas and in human thoracic aortic aneurysms. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of\n              <jats:italic>Fbln4<\/jats:italic>\n              sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of\n              <jats:italic>Thbs1<\/jats:italic>\n              in\n              <jats:italic>SMKO<\/jats:italic>\n              mice prevented the aneurysm formation in \u224880% of\n              <jats:italic>DKO<\/jats:italic>\n              (SMKO;Thbs1 knockout) animals and suppressed Ssh1 (slingshot-1) and cofilin dephosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in\n              <jats:italic>DKO<\/jats:italic>\n              aortas, and mechanical testing showed that structural and material properties of\n              <jats:italic>DKO<\/jats:italic>\n              aortas were markedly improved.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.118.313105","type":"journal-article","created":{"date-parts":[[2018,9,17]],"date-time":"2018-09-17T18:25:10Z","timestamp":1537208710000},"page":"660-672","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":79,"title":["Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans"],"prefix":"10.1161","volume":"123","author":[{"given":"Yoshito","family":"Yamashiro","sequence":"first","affiliation":[{"name":"From the Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (Y.Y., S.J.S., K.S., H.Y.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bui Quoc","family":"Thang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery (B.Q.T., C.T., H.S., M.O., Y.H.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Jae","family":"Shin","sequence":"additional","affiliation":[{"name":"From the Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (Y.Y., S.J.S., K.S., H.Y.)"},{"name":"Graduate School of Life and Environmental Sciences (S.J.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline Antunes","family":"Lino","sequence":"additional","affiliation":[{"name":"University of Tsukuba, Ibaraki, Japan; Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil (C.A.L.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kansai Medical University, Osaka, Japan (T.N.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungsil","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Mechanical 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