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Fibrillin-1 regulates endothelial sprouting during angiogenesis

dc.rights.licenseopenen_US
dc.contributor.authorALONSO, F.
dc.contributor.authorDONG, Y.
dc.contributor.authorLI, L.
dc.contributor.authorJAHJAH, T.
dc.contributor.authorDUPUY, J.-W.
dc.contributor.authorFREMAUX, I.
dc.contributor.authorREINHARDT, D.P.
dc.contributor.authorGÉNOT, E.
dc.date.accessioned2024-10-25T12:12:33Z
dc.date.available2024-10-25T12:12:33Z
dc.date.issued2023
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/202822
dc.description.abstractEnFibrillin-1 is an extracellular matrix protein that assembles into microfibrils which provide critical functions in large blood vessels and other tissues. Mutations in the fibrillin-1 gene are associated with cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Here, we reveal that fibrillin-1 is critical for angiogenesis which is compromised by a typical Marfan mutation. In the mouse retina vascularization model, fibrillin-1 is present in the extracellular matrix at the angiogenic front where it colocalizes with microfibril-associated glycoprotein-1, MAGP1. In Fbn1C1041G/+ mice, a model of Marfan syndrome, MAGP1 deposition is reduced, endothelial sprouting is decreased, and tip cell identity is impaired. Cell culture experiments confirmed that fibrillin-1 deficiency alters vascular endothelial growth factor-A/Notch and Smad signaling which regulate the acquisition of endothelial tip cell/stalk cell phenotypes, and we showed that modulation of MAGP1 expression impacts these pathways. Supplying the growing vasculature of Fbn1C1041G/+ mice with a recombinant C-terminal fragment of fibrillin-1 corrects all defects. Mass spectrometry analyses showed that the fibrillin-1 fragment alters the expression of various proteins including ADAMTS1, a tip cell metalloprotease and matrix-modifying enzyme. Our data establish that fibrillin-1 is a dynamic signaling platform in the regulation of cell specification and matrix remodeling at the angiogenic front and that mutant fibrillin-1-induced defects can be rescued pharmacologically using a C-terminal fragment of the protein. These findings, identify fibrillin-1, MAGP1, and ADAMTS1 in the regulation of endothelial sprouting, and contribute to our understanding of how angiogenesis is regulated. This knowledge may have critical implications for people with Marfan syndrome. Copyright © 2023 the Author(s). Published by PNAS.
dc.language.isoENen_US
dc.title.enFibrillin-1 regulates endothelial sprouting during angiogenesis
dc.typeArticle de revueen_US
dc.identifier.doi10.1073/pnas.2221742120en_US
dc.subject.halSciences du Vivant [q-bio]en_US
bordeaux.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
bordeaux.volume120en_US
bordeaux.hal.laboratoriesBioingénierie Tissulaire (BioTis) - U1026en_US
bordeaux.issue23en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionCNRSen_US
bordeaux.institutionINSERMen_US
bordeaux.institutionCHU de Bordeauxen_US
bordeaux.institutionInstitut Bergoniéen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
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hal.popularnonen_US
hal.audienceInternationaleen_US
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dc.rights.ccPas de Licence CCen_US
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