{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:41:19Z","timestamp":1768527679878,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,3]]},"group-title":"Cell Biology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    Thoracic aortic aneurysm and dissection (TAAD) are major complications of Loeys- Dietz syndrome caused by heterozygous\n                    <jats:italic>TGFB2<\/jats:italic>\n                    mutations. While\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    knockout mice die at birth and adult heterozygotes develop late, non-dissecting or non-rupturing aneurysms, the role of vascular smooth muscle cell (SMC)\u2013derived TGF\u03b22 in postnatal aortic homeostasis and disease remains undefined.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Approach and Results<\/jats:title>\n                  <jats:p>\n                    We generated tamoxifen-inducible, SMC-specific\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    conditional knockout mice (\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    cKO) by crossing\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    <jats:sup>flox<\/jats:sup>\n                    alleles with\n                    <jats:italic>Myh11CreER<\/jats:italic>\n                    <jats:sup>T2<\/jats:sup>\n                    and\n                    <jats:italic>ROSA<\/jats:italic>\n                    <jats:sup>mT\/mG<\/jats:sup>\n                    lineage reporter mice.\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    deletion was induced at 4 weeks of age.\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    cKO mice developed rapidly progressive aneurysms involving both ascending and descending aortas, with intramural dissection and\/or rupture at the proximal descending aorta. Lineage tracing confirmed loss of\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    -deficient SMCs during disease progression. Histological and morphometric analyses revealed elastic fiber fragmentation, SMC loss and de-differentiation, medial thickening, adventitial fibrosis, and accumulation of collagen and proteoglycans. Molecular profiling demonstrated reduced expression of SMC contractile genes (\n                    <jats:italic>Acta2, Myh11<\/jats:italic>\n                    ), increased fibrillar collagen (\n                    <jats:italic>Col1a1<\/jats:italic>\n                    ) expression, early suppression of SMAD2\/3 phosphorylation and increased non-canonical TGF\u03b2 signaling via p38 and pERK1\/2 MAPK pathways.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    These findings demonstrate that TGF\u03b22 derived from vascular SMCs is essential for postnatal aortic wall homeostasis by preserving SMC differentiation, maintaining extracellular matrix integrity, and supporting and preserving a proper balance of both canonical and non-canonical TGF\u03b2 signaling. Loss of SMC-specific\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    precipitates medial degeneration, aneurysm formation, dissection, and rupture, providing direct mechanistic insight into\n                    <jats:italic>TGFB2<\/jats:italic>\n                    -associated aortopathy and establishing a robust novel genetic mouse model for evaluating targeted therapies in TAAD.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        Postnatal, SMC-specific\n                        <jats:italic>Tgfb2<\/jats:italic>\n                        deletion in mice caused rapidly progressive thoracic aortic aneurysms, dissections, and fatal rupture.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Loss of\n                        <jats:italic>Tgfb2<\/jats:italic>\n                        disrupts SMC contractile phenotype and ECM homeostasis, leading to medial degeneration, elastin fragmentation, and abnormal collagen\/proteoglycan accumulation.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Canonical TGF\u03b2\u2013SMAD signaling is suppressed, while MAPK pathways are activated, indicating ligand-specific signaling imbalance.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Findings highlight TGF\u03b22 as a central regulator of postnatal aortic homeostasis and suggest that targeted ligand-specific therapeutic strategies may better preserve aortic wall stability.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>This study identifies smooth muscle cell\u2013derived TGF\u03b22 as a critical, nonredundant regulator of postnatal aortic wall integrity, linking its loss to thoracic aortic aneurysm, dissection, and rupture, and highlighting TGF\u03b22 ligand-specific signaling as a targeted therapeutic target.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:p>\n                    Smooth muscle cell\u2013derived TGF\u03b22 maintains postnatal aortic wall homeostasis by preserving contractile gene expression, elastin architecture, and balanced ECM remodeling. Conditional deletion of\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    in SMCs shifts signaling from canonical SMAD2\/3 to MAPK pathways, leading to medial degeneration, progressive aneurysm, dissection, and rupture\u2014highlighting TGF\u03b22 as a nonredundant, ligand-specific regulator and potential therapeutic target in thoracic aortopathy.\n                  <\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"679917v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.01.679917","type":"posted-content","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T22:45:12Z","timestamp":1759531512000},"source":"Crossref","is-referenced-by-count":0,"title":["Smooth Muscle Cell-Specific TGF\u03b22 Protects Against Thoracic Aortic Aneurysm and Dissection in Mice"],"prefix":"10.64898","author":[{"given":"Mengistu G.","family":"Gebere","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2681-6134","authenticated-orcid":false,"given":"Mrinmay","family":"Chakrabarti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aamina","family":"Azhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3884-9635","authenticated-orcid":false,"given":"Xiaoqin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4889-6542","authenticated-orcid":false,"given":"Narendra R.","family":"Vyavahare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9228-8096","authenticated-orcid":false,"given":"Mohamad","family":"Azhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025100705100578000_2025.10.01.679917v1.1","doi-asserted-by":"crossref","unstructured":"Isselbacher EM , Preventza O , Hamilton Black J , 3rd, Augoustides JG , Beck AW , Bolen MA , Braverman AC , Bray BE , Brown-Zimmerman MM , Chen EP , Collins TJ , DeAnda A, Jr. , Fanola CL , Girardi LN , Hicks CW , Hui DS , Schuyler Jones W , Kalahasti V , Kim KM , Milewicz DM , Oderich GS , Ogbechie L , Promes SB , Gyang Ross E , Schermerhorn ML , Singleton Times S , Tseng EE , Wang GJ , Woo YJ and Peer Review Committee M. 2022 ACC\/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association\/American College of Cardiology Joint Committee on Clinical Practice Guidelines. 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