Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation

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• dc.contributor.author Arribas, Víctor
• dc.contributor.author Onetti, Yara
• dc.contributor.author Ramiro Pareta, Marina
• dc.contributor.author Villacampa, Pilar
• dc.contributor.author Beck, Heike
• dc.contributor.author Alberola i Pla, Mariona
• dc.contributor.author Esteve-Codina, Anna
• dc.contributor.author Merkel, Angelika
• dc.contributor.author Sperandio, Markus
• dc.contributor.author Martínez Estrada, Ofelia M.
• dc.contributor.author Schmid, Bettina
• dc.contributor.author Montanez, Eloi
• dc.date.accessioned 2024-07-31T12:03:55Z
• dc.date.available 2024-07-31T12:03:55Z
• dc.date.issued 2024
• dc.description.abstract TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that regulates gene expression, and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its roles in endothelial cells (ECs), angiogenesis, and vascular function. Using inducible EC-specific TDP-43-KO mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity, and blood vessel stability. Postnatal EC-specific deletion of TDP-43 led to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the CNS with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted the fibronectin matrix around sprouting vessels and reduced β-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature.
• dc.description.sponsorship This work has been funded by the Spanish Ministry of Science, Innovation and Universities (PID2019-108902GB-I00 and PID2022-141840OB-I00) and the Fundació la Marato TV3 (202327-10). PV is supported by PID2021-124400OA-I00, OMME is supported by PID2020-119315GB-I00, and MS is supported by German Research Foundation (DFG) grants TRR359 (491676693) project B02 and TRR332 (449437943) project C02.
• dc.format.mimetype application/pdf
• dc.identifier.citation Arribas V, Onetti Y, Ramiro-Pareta M, Villacampa P, Beck H, Alberola M, et al. Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation. JCI Insight. 2024 Feb 1;9(5):e177819. DOI: 10.1172/jci.insight.177819
• dc.identifier.doi http://dx.doi.org/10.1172/jci.insight.177819
• dc.identifier.issn 2379-3708
• dc.identifier.uri http://hdl.handle.net/10230/60866
• dc.language.iso eng
• dc.publisher American Society for Clinical Investigation
• dc.relation.ispartof JCI Insight. 2024 Feb 1;9(5):e177819
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-108902GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-141840OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124400OA-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119315GB-I00
• dc.rights © 2024, Arribas et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Angiogenesis
• dc.subject.keyword Endothelial cells
• dc.subject.keyword Vascular biology
• dc.title Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion