Structural and transcriptomic alterations underlying the progression of aortic dissection in Fbn1G234D/G234D mice

Structural and transcriptomic alterations underlying the progression of aortic dissection in Fbn1G234D/G234D mice | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Structural and transcriptomic alterations underlying the progression of aortic dissection in Fbn1 G234D/G234D mice Md Al Amin Sheikh, Kenichi Kimura, Eri Motoyama, Keiichi Asano, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8556610/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aortic dissection (AD) is characterized by separation within the medial layers of the aortic wall. Pathogenic variants in the fibrillin-1 gene (FBN1), which cause Marfan syndrome, represent a major genetic cause of AD. In a recently established Fbn1G234D/G234D mouse model, intimomedial tears develop at 3 weeks of age, and 50% of mice die by 5 weeks from aortic rupture. Despite this severe phenotype, the magnitude and expansion of AD lesions, as well as the molecular alterations within the medial layers remain incompletely understood. In this study, we used three-dimensional propagation-based X-ray phase-contrast synchrotron imaging for reconstruction of the ascending aortas, together with single-cell RNA sequencing (scRNA-seq) analysis in Fbn1G234D/G234D mice. Synchrotron imaging revealed 1-2 elastic lamellar breaks evolved into widespread disruptions spanning the entire elastic lamellae, accompanied by localized adventitial thickening. scRNA-seq analysis followed by immunofluorescence staining showed upregulation of fibronectin (Fn1) upregulation in Fbn1G234D/G234D smooth muscle cells (SMCs). Consistently, increased FN1 expression was observed in human non-heritable AD samples. Furthermore, enhanced expression of fibronectin receptors and activation of focal adhesion kinase signaling suggested augmented extracellular matrix–SMC interactions during disease progression. These findings indicate that AD progression involves coordinated medial structural failure, adventitial remodeling, and fibronectin-associated SMC dysfunction. Biological sciences/Cell biology/Mechanisms of disease Health sciences/Diseases/Cardiovascular diseases/Vascular diseases/Aortic diseases Full Text Additional Declarations There is NO Competing Interest. Supplementary Files V8SheikhSupplementalMaterials.pdf Supplemental table and figures Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8556610","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":580423808,"identity":"4f2a9840-c26c-4c01-a3d4-080e129d0b80","order_by":0,"name":"Md Al Amin Sheikh","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Md","middleName":"Al Amin","lastName":"Sheikh","suffix":""},{"id":580423807,"identity":"9f84ef71-6821-4cd2-8da6-7eb939af00bd","order_by":1,"name":"Kenichi 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Pathogenic variants in the fibrillin-1 gene (FBN1), which cause Marfan syndrome, represent a major genetic cause of AD. In a recently established Fbn1G234D/G234D mouse model, intimomedial tears develop at 3 weeks of age, and 50% of mice die by 5 weeks from aortic rupture. Despite this severe phenotype, the magnitude and expansion of AD lesions, as well as the molecular alterations within the medial layers remain incompletely understood. In this study, we used three-dimensional propagation-based X-ray phase-contrast synchrotron imaging for reconstruction of the ascending aortas, together with single-cell RNA sequencing (scRNA-seq) analysis in Fbn1G234D/G234D mice. 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