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

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...

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Autores: Arribas, Víctor, Onetti Vilalta, Yara, Ramiro Pareta, Marina|||0000-0002-9017-4981, Villacampa, Pilar|||0000-0002-2860-7475, Beck, Heike, Alberola, Mariona, Esteve-Codina, Anna|||0000-0003-0361-2873, Merkel, Angelika|||0000-0001-5164-6803, Sperandio, Markus|||0000-0002-7689-3613, Martínez-Estrada, Ofelia M.|||0000-0002-1814-1974, Schmid, Bettina, Montanez, Eloi|||0000-0003-4059-5056
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:301940
Acceso en línea:https://ddd.uab.cat/record/301940
https://dx.doi.org/urn:doi:10.1172/jci.insight.177819
Access Level:acceso abierto
Palabra clave:Angiogenesis
Animals
DNA-Binding Proteins
Endothelial Cells
Mice
Neovascularization, Physiologic
Neuroinflammatory Diseases
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spelling Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammationArribas, VíctorOnetti Vilalta, YaraRamiro Pareta, Marina|||0000-0002-9017-4981Villacampa, Pilar|||0000-0002-2860-7475Beck, HeikeAlberola, MarionaEsteve-Codina, Anna|||0000-0003-0361-2873Merkel, Angelika|||0000-0001-5164-6803Sperandio, Markus|||0000-0002-7689-3613Martínez-Estrada, Ofelia M.|||0000-0002-1814-1974Schmid, BettinaMontanez, Eloi|||0000-0003-4059-5056AngiogenesisAnimalsDNA-Binding ProteinsEndothelial CellsMiceNeovascularization, PhysiologicNeuroinflammatory DiseasesTAR 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. 22024-01-0120242024-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/301940https://dx.doi.org/urn:doi:10.1172/jci.insight.177819reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-108902GB-I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-141840OB-I00Fundació la Marató de TV3 https://doi.org/10.13039/100008666 202327-10Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-119315GB-I00open accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3019402026-06-06T12:50:31Z
dc.title.none.fl_str_mv Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
title Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
spellingShingle Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
Arribas, Víctor
Angiogenesis
Animals
DNA-Binding Proteins
Endothelial Cells
Mice
Neovascularization, Physiologic
Neuroinflammatory Diseases
title_short Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
title_full Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
title_fullStr Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
title_full_unstemmed Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
title_sort Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
dc.creator.none.fl_str_mv Arribas, Víctor
Onetti Vilalta, Yara
Ramiro Pareta, Marina|||0000-0002-9017-4981
Villacampa, Pilar|||0000-0002-2860-7475
Beck, Heike
Alberola, Mariona
Esteve-Codina, Anna|||0000-0003-0361-2873
Merkel, Angelika|||0000-0001-5164-6803
Sperandio, Markus|||0000-0002-7689-3613
Martínez-Estrada, Ofelia M.|||0000-0002-1814-1974
Schmid, Bettina
Montanez, Eloi|||0000-0003-4059-5056
author Arribas, Víctor
author_facet Arribas, Víctor
Onetti Vilalta, Yara
Ramiro Pareta, Marina|||0000-0002-9017-4981
Villacampa, Pilar|||0000-0002-2860-7475
Beck, Heike
Alberola, Mariona
Esteve-Codina, Anna|||0000-0003-0361-2873
Merkel, Angelika|||0000-0001-5164-6803
Sperandio, Markus|||0000-0002-7689-3613
Martínez-Estrada, Ofelia M.|||0000-0002-1814-1974
Schmid, Bettina
Montanez, Eloi|||0000-0003-4059-5056
author_role author
author2 Onetti Vilalta, Yara
Ramiro Pareta, Marina|||0000-0002-9017-4981
Villacampa, Pilar|||0000-0002-2860-7475
Beck, Heike
Alberola, Mariona
Esteve-Codina, Anna|||0000-0003-0361-2873
Merkel, Angelika|||0000-0001-5164-6803
Sperandio, Markus|||0000-0002-7689-3613
Martínez-Estrada, Ofelia M.|||0000-0002-1814-1974
Schmid, Bettina
Montanez, Eloi|||0000-0003-4059-5056
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Angiogenesis
Animals
DNA-Binding Proteins
Endothelial Cells
Mice
Neovascularization, Physiologic
Neuroinflammatory Diseases
topic Angiogenesis
Animals
DNA-Binding Proteins
Endothelial Cells
Mice
Neovascularization, Physiologic
Neuroinflammatory Diseases
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2
2024-01-01
2024
2024-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/301940
https://dx.doi.org/urn:doi:10.1172/jci.insight.177819
url https://ddd.uab.cat/record/301940
https://dx.doi.org/urn:doi:10.1172/jci.insight.177819
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2019-108902GB-I00
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-141840OB-I00
Fundació la Marató de TV3 https://doi.org/10.13039/100008666 202327-10
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-119315GB-I00
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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