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Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2

Soluble epoxide hydrolase (sEH) is upregulated in microvascular endothelium of human brain with vascular cognitive impairment (VCI). Transgenic endothelial expression of human sEH in mice (Tie2hsEH) induces endothelial dysfunction (ED), a pathogenetic mechanism of VCI. We sought to determine if endo...

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Autores principales: Davis, Catherine M., Zhang, Wenri H., Bah, Thierno M., Roese, Natalie E., Allen, Elyse M., Leung, Philberta, Boutros, Sydney J., Marzulla, Tessa, Patel, Esha, Nie, Xiao, Alkayed, Farah N., Huang, Justin H., Jensen, Michael A., Raber, Jacob, Pike, Martin M., Alkayed, Nabil J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9256583/
https://www.ncbi.nlm.nih.gov/pubmed/35927273
http://dx.doi.org/10.1038/s41514-022-00090-1
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author Davis, Catherine M.
Zhang, Wenri H.
Bah, Thierno M.
Roese, Natalie E.
Allen, Elyse M.
Leung, Philberta
Boutros, Sydney J.
Marzulla, Tessa
Patel, Esha
Nie, Xiao
Alkayed, Farah N.
Huang, Justin H.
Jensen, Michael A.
Raber, Jacob
Pike, Martin M.
Alkayed, Nabil J.
author_facet Davis, Catherine M.
Zhang, Wenri H.
Bah, Thierno M.
Roese, Natalie E.
Allen, Elyse M.
Leung, Philberta
Boutros, Sydney J.
Marzulla, Tessa
Patel, Esha
Nie, Xiao
Alkayed, Farah N.
Huang, Justin H.
Jensen, Michael A.
Raber, Jacob
Pike, Martin M.
Alkayed, Nabil J.
author_sort Davis, Catherine M.
collection PubMed
description Soluble epoxide hydrolase (sEH) is upregulated in microvascular endothelium of human brain with vascular cognitive impairment (VCI). Transgenic endothelial expression of human sEH in mice (Tie2hsEH) induces endothelial dysfunction (ED), a pathogenetic mechanism of VCI. We sought to determine if endothelial upregulation of sEH is sufficient to cause cognitive impairment, and if cognitive impairment due to chronic hypoperfusion induced by unilateral common carotid artery occlusion (CCAO) is exacerbated in Tie2hsEH mice. Behavioral performance was assessed by the open field, rotarod, novel object, Morris water maze and fear conditioning tests. Cerebral blood flow and brain morphology were evaluated by MRI, and inflammatory changes investigated using immunohistochemistry and flow cytometry. We demonstrate that transgenic endothelial expression of sEH is sufficient to induce cognitive impairment, associated with leukocyte infiltration, brain atrophy and accelerated, age-dependent ventriculomegaly, identifying ED and sEH upregulation as potential underlying mechanisms and therapeutic targets for VCI.
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spelling pubmed-92565832022-07-07 Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2 Davis, Catherine M. Zhang, Wenri H. Bah, Thierno M. Roese, Natalie E. Allen, Elyse M. Leung, Philberta Boutros, Sydney J. Marzulla, Tessa Patel, Esha Nie, Xiao Alkayed, Farah N. Huang, Justin H. Jensen, Michael A. Raber, Jacob Pike, Martin M. Alkayed, Nabil J. NPJ Aging Article Soluble epoxide hydrolase (sEH) is upregulated in microvascular endothelium of human brain with vascular cognitive impairment (VCI). Transgenic endothelial expression of human sEH in mice (Tie2hsEH) induces endothelial dysfunction (ED), a pathogenetic mechanism of VCI. We sought to determine if endothelial upregulation of sEH is sufficient to cause cognitive impairment, and if cognitive impairment due to chronic hypoperfusion induced by unilateral common carotid artery occlusion (CCAO) is exacerbated in Tie2hsEH mice. Behavioral performance was assessed by the open field, rotarod, novel object, Morris water maze and fear conditioning tests. Cerebral blood flow and brain morphology were evaluated by MRI, and inflammatory changes investigated using immunohistochemistry and flow cytometry. We demonstrate that transgenic endothelial expression of sEH is sufficient to induce cognitive impairment, associated with leukocyte infiltration, brain atrophy and accelerated, age-dependent ventriculomegaly, identifying ED and sEH upregulation as potential underlying mechanisms and therapeutic targets for VCI. Nature Publishing Group UK 2022-07-05 /pmc/articles/PMC9256583/ /pubmed/35927273 http://dx.doi.org/10.1038/s41514-022-00090-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Davis, Catherine M.
Zhang, Wenri H.
Bah, Thierno M.
Roese, Natalie E.
Allen, Elyse M.
Leung, Philberta
Boutros, Sydney J.
Marzulla, Tessa
Patel, Esha
Nie, Xiao
Alkayed, Farah N.
Huang, Justin H.
Jensen, Michael A.
Raber, Jacob
Pike, Martin M.
Alkayed, Nabil J.
Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2
title Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2
title_full Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2
title_fullStr Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2
title_full_unstemmed Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2
title_short Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2
title_sort age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human ephx2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9256583/
https://www.ncbi.nlm.nih.gov/pubmed/35927273
http://dx.doi.org/10.1038/s41514-022-00090-1
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