{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T19:00:36Z","timestamp":1784746836705,"version":"3.55.0"},"reference-count":75,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Individuals with Loeys-Dietz syndrome 3 are at risk for thoracic aortic dissection even if their aortas are not substantially dilated. A pathogenic variant of SMAD3 is a genetic trigger, but the cellular programs that underlie the heightened aortic risk remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We ascertained the cardiovascular profile of 57 individuals in a 4-generation family with a missense variant in SMAD3 (p.Arg287Gln). Aortic medial architectures were quantified from aortas harvested during thoracic aortic replacement surgery, with 2-dimensional and 3-dimensional profiling of the elastin-microfibril network. TGF-\u03b2 (transforming growth factor beta)-dependent regulatory networks were investigated by whole-genome RNA sequencing of ascending aortic smooth muscle cells (SMCs) and bioinformatics-informed chromatin immunoprecipitation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Cardiovascular phenotypes of family members harboring the SMAD3 variant included thoracic aortopathy, peripheral artery aneurysms and tortuosity, cerebrovascular disease, coronary artery dissections, and mitral valve prolapse. The median age at the first aortic event was 36.5 years. Ascending aortas were less dilated than the aortic root, with relatively intact lamellar structure and SMC content. However, early pathology was evident, with SMCs separated from elastic lamellae by a thin layer of glycosaminoglycans. Confocal reconstructions revealed that elastic fibers were poorly decorated by microfibrils, with reduced fibrillin-1, fibrillin-2, microfibril associated glycoprotein-2, fibulin-1 and fibulin-2. RNA sequencing of Loeys-Dietz syndrome 3 SMCs revealed reduced microfibril gene expression. Furthermore, PRRX2 (paired related homeobox 2) was found to be downregulated in Loeys-Dietz syndrome 3 SMCs in culture and in situ, occupies gene promoter sites for all 5 microfibrils, and mediates their expression in SMCs. SMAD3 overexpression rescued both\n                      <jats:italic toggle=\"yes\">PRRX2<\/jats:italic>\n                      and microfibril expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These findings identify SMCs delaminating from unsheathed elastic fibers as an incipient pathological program in Loeys-Dietz syndrome 3 aortas. They also uncover a SMAD3-PRRX2-microfibril axis that, being perturbed, could explain this disconnection phenomenon and contribute to risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324690","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T09:00:34Z","timestamp":1781168434000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Microfibril Denudation Marks Early Aortic Vulnerability in SMAD3 Variant Carriers: A Multigenerational Study"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3231-3020","authenticated-orcid":true,"given":"Paulina M.","family":"Kowalewska","sequence":"first","affiliation":[{"name":"Robarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, 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