FOXO1 unlocks SMAD function to drive mechano-induced endothelial-to-mesenchymal transition

FOXO1 unlocks SMAD function to drive mechano-induced endothelial-to-mesenchymal transition | 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 FOXO1 unlocks SMAD function to drive mechano-induced endothelial-to-mesenchymal transition Petra Knaus, Paul Mendez, Lion Raaz, Yunyun Xiao, Jerome Jatzlau, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8347032/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Endothelial-to-mesenchymal transition (EndMT) contributes to vascular remodeling and endothelial dysfunction in diseases such as atherosclerosis and pulmonary arterial hypertension. This process describes a gradual shift in which endothelial cells (ECs) lose expression of classical EC markers and acquire mesenchymal-like gene expression patterns and phenotypic traits. Although SMAD transcription factors are key regulators of EndMT, driven by mechanical cues from disturbed flow that activate BMP or TGFβ signaling, their weak DNA-binding affinity invoked the need for additional transcriptional co-factors to specify gene targets under pathophysiological flow conditions. Here, we identified FOXO1 as a transcriptional co-factor that cooperates with SMADs to regulate mesenchymal gene expression in ECs exposed to irregular flow. FOXO1 and SMADs co-occupy genomic loci and form transcriptional complexes. Although SMAD DNA binding is FOXO1-independent, FOXO1 activity is required for full induction of SMAD target genes. Notably, FOXO1 DNA-binding activity is essential for robust activation of EndMT-associated genes, as both pharmacological inhibition and siRNA-mediated depletion of FOXO1 attenuate SMAD target gene expression. Functionally, combined targeting of FOXO1 and SMAD signaling rescues EndMT-associated endothelial dysfunction in carotid arteries of mice. Our results describe FOXO1 as key integrator of SMAD-mediated EndMT signaling, linking it to pathogenic SMAD activation in disease contexts. Biological sciences/Cell biology/Mechanisms of disease Biological sciences/Molecular biology/Transcription Full Text Additional Declarations There is NO Competing Interest. Supplementary Files 251206supplementarymaterial.docx Dasteht 1 Mendezetalsupplementarytable1.xlsx Dataset 1 Cite Share Download PDF Status: Under Review 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-8347032","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":574035774,"identity":"534a0b7f-55e2-4729-8a92-fe9f079f429c","order_by":0,"name":"Petra 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Notably, FOXO1 DNA-binding activity is essential for robust activation of EndMT-associated genes, as both pharmacological inhibition and siRNA-mediated depletion of FOXO1 attenuate SMAD target gene expression. Functionally, combined targeting of FOXO1 and SMAD signaling rescues EndMT-associated endothelial dysfunction in carotid arteries of mice. 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