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| Pàgina inicial > Articles > Articles publicats > Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation |
(Universitat de Barcelona. Institut de Biomedicina) (Institut d'Investigació Biomèdica de Bellvitge) (Centre de Regulació Genòmica) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Ludwig-Maximilians-University Munich) (Universitat de Barcelona) (Institut d'Investigació Biomèdica de Bellvitge)
| Data: | 2024 |
| Resum: | 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. |
| Ajuts: | Agencia Estatal de Investigación PID2019-108902GB-I00 Agencia Estatal de Investigación PID2022-141840OB-I00 Fundació la Marató de TV3 202327-10 Agencia Estatal de Investigación PID2020-119315GB-I00 |
| Nota: | We are grateful for the excellent technical support provided by the Science and Technology Centers of the University of Barcelona at the Bellvitge Campus. 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. |
| Nota: | We are grateful for the excellent technical support provided by the Science and Technology Centers of the University of Barcelona at the Bellvitge Campus. This work has been funded by the Spanish Ministry of Science, Innovation and Universities (PID2019-108902GB-I00 and PID2022-141840OB-I00) and the Fun-dació 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. |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Angiogenesis ; Animals ; DNA-Binding Proteins ; Endothelial Cells ; Mice ; Neovascularization, Physiologic ; Neuroinflammatory Diseases |
| Publicat a: | JCI insight, Vol. 9 Núm. 5 (2024) , p. e177819, ISSN 2379-3708 |
