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Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes

Sufficient vascular supply is indispensable for brain development and function, whereas dysfunctional blood vessels are associated with human diseases such as vascular malformations, stroke or neurodegeneration. Pericytes are capillary-associated mesenchymal cells that limit vascular permeability an...

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Autores principales: Diéguez-Hurtado, Rodrigo, Kato, Katsuhiro, Giaimo, Benedetto Daniele, Nieminen-Kelhä, Melina, Arf, Hendrik, Ferrante, Francesca, Bartkuhn, Marek, Zimmermann, Tobias, Bixel, M. Gabriele, Eilken, Hanna M., Adams, Susanne, Borggrefe, Tilman, Vajkoczy, Peter, Adams, Ralf H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597568/
https://www.ncbi.nlm.nih.gov/pubmed/31249304
http://dx.doi.org/10.1038/s41467-019-10643-w
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author Diéguez-Hurtado, Rodrigo
Kato, Katsuhiro
Giaimo, Benedetto Daniele
Nieminen-Kelhä, Melina
Arf, Hendrik
Ferrante, Francesca
Bartkuhn, Marek
Zimmermann, Tobias
Bixel, M. Gabriele
Eilken, Hanna M.
Adams, Susanne
Borggrefe, Tilman
Vajkoczy, Peter
Adams, Ralf H.
author_facet Diéguez-Hurtado, Rodrigo
Kato, Katsuhiro
Giaimo, Benedetto Daniele
Nieminen-Kelhä, Melina
Arf, Hendrik
Ferrante, Francesca
Bartkuhn, Marek
Zimmermann, Tobias
Bixel, M. Gabriele
Eilken, Hanna M.
Adams, Susanne
Borggrefe, Tilman
Vajkoczy, Peter
Adams, Ralf H.
author_sort Diéguez-Hurtado, Rodrigo
collection PubMed
description Sufficient vascular supply is indispensable for brain development and function, whereas dysfunctional blood vessels are associated with human diseases such as vascular malformations, stroke or neurodegeneration. Pericytes are capillary-associated mesenchymal cells that limit vascular permeability and protect the brain by preserving blood-brain barrier integrity. Loss of pericytes has been linked to neurodegenerative changes in genetically modified mice. Here, we report that postnatal inactivation of the Rbpj gene, encoding the transcription factor RBPJ, leads to alteration of cell identity markers in brain pericytes, increases local TGFβ signalling, and triggers profound changes in endothelial behaviour. These changes, which are not mimicked by pericyte ablation, imperil vascular stability and induce the acquisition of pathological landmarks associated with cerebral cavernous malformations. In adult mice, loss of Rbpj results in bigger stroke lesions upon ischemic insult. We propose that brain pericytes can acquire deleterious properties that actively enhance vascular lesion formation and promote pathogenic processes.
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spelling pubmed-65975682019-07-01 Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes Diéguez-Hurtado, Rodrigo Kato, Katsuhiro Giaimo, Benedetto Daniele Nieminen-Kelhä, Melina Arf, Hendrik Ferrante, Francesca Bartkuhn, Marek Zimmermann, Tobias Bixel, M. Gabriele Eilken, Hanna M. Adams, Susanne Borggrefe, Tilman Vajkoczy, Peter Adams, Ralf H. Nat Commun Article Sufficient vascular supply is indispensable for brain development and function, whereas dysfunctional blood vessels are associated with human diseases such as vascular malformations, stroke or neurodegeneration. Pericytes are capillary-associated mesenchymal cells that limit vascular permeability and protect the brain by preserving blood-brain barrier integrity. Loss of pericytes has been linked to neurodegenerative changes in genetically modified mice. Here, we report that postnatal inactivation of the Rbpj gene, encoding the transcription factor RBPJ, leads to alteration of cell identity markers in brain pericytes, increases local TGFβ signalling, and triggers profound changes in endothelial behaviour. These changes, which are not mimicked by pericyte ablation, imperil vascular stability and induce the acquisition of pathological landmarks associated with cerebral cavernous malformations. In adult mice, loss of Rbpj results in bigger stroke lesions upon ischemic insult. We propose that brain pericytes can acquire deleterious properties that actively enhance vascular lesion formation and promote pathogenic processes. Nature Publishing Group UK 2019-06-27 /pmc/articles/PMC6597568/ /pubmed/31249304 http://dx.doi.org/10.1038/s41467-019-10643-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Diéguez-Hurtado, Rodrigo
Kato, Katsuhiro
Giaimo, Benedetto Daniele
Nieminen-Kelhä, Melina
Arf, Hendrik
Ferrante, Francesca
Bartkuhn, Marek
Zimmermann, Tobias
Bixel, M. Gabriele
Eilken, Hanna M.
Adams, Susanne
Borggrefe, Tilman
Vajkoczy, Peter
Adams, Ralf H.
Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes
title Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes
title_full Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes
title_fullStr Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes
title_full_unstemmed Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes
title_short Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes
title_sort loss of the transcription factor rbpj induces disease-promoting properties in brain pericytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597568/
https://www.ncbi.nlm.nih.gov/pubmed/31249304
http://dx.doi.org/10.1038/s41467-019-10643-w
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