Mutation of platelet-derived growth factor receptor β causes and exacerbates the severity of brain arteriovenous malformation through enhancing angiogenesis

Mutation of platelet-derived growth factor receptor β causes and exacerbates the severity of brain arteriovenous malformation through enhancing angiogenesis | 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 Research Article Mutation of platelet-derived growth factor receptor β causes and exacerbates the severity of brain arteriovenous malformation through enhancing angiogenesis Alka Yadav, Leandro Barbosa Do Prado, Mustafa Mohamed, Calvin Wang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7552935/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 May, 2026 Read the published version in Angiogenesis → Version 1 posted 17 You are reading this latest preprint version Abstract Brain arteriovenous malformations (bAVMs) are tangles of abnormal vessels that shunt blood directly from arteries to Veins. The reduction of pericytes is linked to hemorrhage in bAVMs. The PDGFB/PDGFRβ signaling pathway is crucial for regulating pericyte recruitment during angiogenesis. Here, we show that mutation of Pdgfrβ causes cerebrovascular malformations in the brain's angiogenic region, associated with increased pro-angiogenic signaling. Interestingly, the expression of activin receptor-like kinase 1 (Alk1) is decreased in the brain's angiogenic region of Pdgfrβ mutant mice. Overexpression of ALK1 in brain endothelial cells (ECs) reduces angiogenic signaling and the severity of vascular malformations in Pdgfrβ mutant mice. Mutation of Pdgfrβ also increases bAVM penetrance in endoglin-deficient mice (a gene that causes AVMs), leading to an increase of dysplastic vessels and microhemorrhages in bAVMs. Our data indicate that Pdgfrβ mutation causes cerebrovascular malformations and worsens the bAVM phenotype in endoglin mutant mice by enhancing angiogenesis, EC proliferation, and inflammation. Overexpression of ALK1 in brain ECs reduces the severity of cerebrovascular malformations in Pdgfrβ mutant mice through downregulating angiogenic signaling. Brain arteriovenous malformation platelet-derived growth factor receptor-β pericyte endoglin Alk1 Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryFile5ForSubmission.docx Cite Share Download PDF Status: Published Journal Publication published 03 May, 2026 Read the published version in Angiogenesis → Version 1 posted Editorial decision: Revision requested 14 Oct, 2025 Reviews received at journal 14 Oct, 2025 Reviews received at journal 10 Oct, 2025 Reviews received at journal 09 Oct, 2025 Reviews received at journal 08 Oct, 2025 Reviews received at journal 30 Sep, 2025 Reviews received at journal 25 Sep, 2025 Reviewers agreed at journal 12 Sep, 2025 Reviewers agreed at journal 11 Sep, 2025 Reviewers agreed at journal 11 Sep, 2025 Reviewers agreed at journal 11 Sep, 2025 Reviewers agreed at journal 11 Sep, 2025 Reviewers agreed at journal 11 Sep, 2025 Reviewers invited by journal 11 Sep, 2025 Editor assigned by journal 08 Sep, 2025 Submission checks completed at journal 08 Sep, 2025 First submitted to journal 06 Sep, 2025 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. 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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-7552935","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":514236222,"identity":"ed387136-048e-4061-b55e-cbbd59b96ad8","order_by":0,"name":"Alka Yadav","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Alka","middleName":"","lastName":"Yadav","suffix":""},{"id":514236223,"identity":"a0d52580-dd26-4b1f-9ad7-c2fbf9d364a3","order_by":1,"name":"Leandro Barbosa Do Prado","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Leandro","middleName":"Barbosa Do","lastName":"Prado","suffix":""},{"id":514236224,"identity":"e7140549-9b7c-432a-9e76-91c4635be5d8","order_by":2,"name":"Mustafa Mohamed","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Mustafa","middleName":"","lastName":"Mohamed","suffix":""},{"id":514236225,"identity":"0fe97ca0-c327-4702-8d2a-d33cb933e9b3","order_by":3,"name":"Calvin Wang","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Calvin","middleName":"","lastName":"Wang","suffix":""},{"id":514236226,"identity":"7d72d799-112b-47be-8a61-509f5ec5412c","order_by":4,"name":"Joshua Shi","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Shi","suffix":""},{"id":514236227,"identity":"ede00e24-867b-4e70-97ac-9e66fb1139c4","order_by":5,"name":"Zahra Shabani","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Zahra","middleName":"","lastName":"Shabani","suffix":""},{"id":514236229,"identity":"b9942473-8f9b-4622-b482-e22423aecf4c","order_by":6,"name":"Rich Liang","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Rich","middleName":"","lastName":"Liang","suffix":""},{"id":514236230,"identity":"a9bf4cfb-ba04-44f1-8f33-67bae4b83c04","order_by":7,"name":"Kelly Press","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Kelly","middleName":"","lastName":"Press","suffix":""},{"id":514236231,"identity":"5c035360-e35b-4b10-828d-824ef7dda83f","order_by":8,"name":"Courtney Tom","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Courtney","middleName":"","lastName":"Tom","suffix":""},{"id":514236232,"identity":"b54ae8c0-68bf-4ed9-bf2a-689b57d38c98","order_by":9,"name":"Ethan A. 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The reduction of pericytes is linked to hemorrhage in bAVMs. The PDGFB/PDGFRβ signaling pathway is crucial for regulating pericyte recruitment during angiogenesis. Here, we show that mutation of \u003cem\u003ePdgfrβ\u003c/em\u003e causes cerebrovascular malformations in the brain's angiogenic region, associated with increased pro-angiogenic signaling. Interestingly, the expression of activin receptor-like kinase 1 (Alk1) is decreased in the brain's angiogenic region of \u003cem\u003ePdgfrβ\u003c/em\u003e mutant mice. Overexpression of ALK1 in brain endothelial cells (ECs) reduces angiogenic signaling and the severity of vascular malformations in \u003cem\u003ePdgfrβ\u003c/em\u003e mutant mice. 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