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Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke

At the blood-brain barrier (BBB), laminin-α5 is predominantly synthesized by endothelial cells and mural cells. Endothelial laminin-α5 is dispensable for BBB maintenance under homeostatic conditions but inhibits inflammatory cell extravasation in pathological conditions. Whether mural cell-derived l...

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Autores principales: Nirwane, Abhijit, Johnson, Jessica, Nguyen, Benjamin, Miner, Jeffrey H., Yao, Yao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378751/
https://www.ncbi.nlm.nih.gov/pubmed/30777135
http://dx.doi.org/10.1186/s40478-019-0676-8
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author Nirwane, Abhijit
Johnson, Jessica
Nguyen, Benjamin
Miner, Jeffrey H.
Yao, Yao
author_facet Nirwane, Abhijit
Johnson, Jessica
Nguyen, Benjamin
Miner, Jeffrey H.
Yao, Yao
author_sort Nirwane, Abhijit
collection PubMed
description At the blood-brain barrier (BBB), laminin-α5 is predominantly synthesized by endothelial cells and mural cells. Endothelial laminin-α5 is dispensable for BBB maintenance under homeostatic conditions but inhibits inflammatory cell extravasation in pathological conditions. Whether mural cell-derived laminin-α5 is involved in vascular integrity regulation, however, remains unknown. To answer this question, we generated transgenic mice with laminin-α5 deficiency in mural cells (α5-PKO). Under homeostatic conditions, no defects in BBB integrity and cerebral blood flow (CBF) were observed in α5-PKO mice, suggesting that mural cell-derived laminin-α5 is dispensable for BBB maintenance and CBF regulation under homeostatic conditions. After ischemia-reperfusion (MCAO) injury, however, α5-PKO mice displayed less severe neuronal injury, including reduced infarct volume, decreased neuronal death, and improved neurological function. In addition, α5-PKO mice also showed attenuated vascular damage (milder BBB disruption, reduced inflammatory cell infiltration, decreased brain edema, and diminished hemorrhagic transformation). Mechanistic studies revealed less severe tight junction protein (TJP) loss and pericyte coverage reduction in α5-PKO mice after ischemia-reperfusion injury, indicating that the attenuated ischemic injury in α5-PKO mice is possibly due to less severe vascular damage. These findings suggest that mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke and that inhibiting its signaling may have a neuroprotective effect. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-019-0676-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-63787512019-02-28 Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke Nirwane, Abhijit Johnson, Jessica Nguyen, Benjamin Miner, Jeffrey H. Yao, Yao Acta Neuropathol Commun Research At the blood-brain barrier (BBB), laminin-α5 is predominantly synthesized by endothelial cells and mural cells. Endothelial laminin-α5 is dispensable for BBB maintenance under homeostatic conditions but inhibits inflammatory cell extravasation in pathological conditions. Whether mural cell-derived laminin-α5 is involved in vascular integrity regulation, however, remains unknown. To answer this question, we generated transgenic mice with laminin-α5 deficiency in mural cells (α5-PKO). Under homeostatic conditions, no defects in BBB integrity and cerebral blood flow (CBF) were observed in α5-PKO mice, suggesting that mural cell-derived laminin-α5 is dispensable for BBB maintenance and CBF regulation under homeostatic conditions. After ischemia-reperfusion (MCAO) injury, however, α5-PKO mice displayed less severe neuronal injury, including reduced infarct volume, decreased neuronal death, and improved neurological function. In addition, α5-PKO mice also showed attenuated vascular damage (milder BBB disruption, reduced inflammatory cell infiltration, decreased brain edema, and diminished hemorrhagic transformation). Mechanistic studies revealed less severe tight junction protein (TJP) loss and pericyte coverage reduction in α5-PKO mice after ischemia-reperfusion injury, indicating that the attenuated ischemic injury in α5-PKO mice is possibly due to less severe vascular damage. These findings suggest that mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke and that inhibiting its signaling may have a neuroprotective effect. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-019-0676-8) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-18 /pmc/articles/PMC6378751/ /pubmed/30777135 http://dx.doi.org/10.1186/s40478-019-0676-8 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Nirwane, Abhijit
Johnson, Jessica
Nguyen, Benjamin
Miner, Jeffrey H.
Yao, Yao
Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
title Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
title_full Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
title_fullStr Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
title_full_unstemmed Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
title_short Mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
title_sort mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378751/
https://www.ncbi.nlm.nih.gov/pubmed/30777135
http://dx.doi.org/10.1186/s40478-019-0676-8
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