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Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model
Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835246/ https://www.ncbi.nlm.nih.gov/pubmed/33495460 http://dx.doi.org/10.1038/s41467-020-20774-0 |
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author | Zhou, Huanjiao Jenny Qin, Lingfeng Jiang, Quan Murray, Katie N. Zhang, Haifeng Li, Busu Lin, Qun Graham, Morven Liu, Xinran Grutzendler, Jaime Min, Wang |
author_facet | Zhou, Huanjiao Jenny Qin, Lingfeng Jiang, Quan Murray, Katie N. Zhang, Haifeng Li, Busu Lin, Qun Graham, Morven Liu, Xinran Grutzendler, Jaime Min, Wang |
author_sort | Zhou, Huanjiao Jenny |
collection | PubMed |
description | Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here we report that mice with a brain EC-specific deletion of Pdcd10 (Pdcd10(BECKO)) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10(BECKO) lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10(BECKO) mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis. |
format | Online Article Text |
id | pubmed-7835246 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78352462021-01-29 Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model Zhou, Huanjiao Jenny Qin, Lingfeng Jiang, Quan Murray, Katie N. Zhang, Haifeng Li, Busu Lin, Qun Graham, Morven Liu, Xinran Grutzendler, Jaime Min, Wang Nat Commun Article Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here we report that mice with a brain EC-specific deletion of Pdcd10 (Pdcd10(BECKO)) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10(BECKO) lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10(BECKO) mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis. Nature Publishing Group UK 2021-01-25 /pmc/articles/PMC7835246/ /pubmed/33495460 http://dx.doi.org/10.1038/s41467-020-20774-0 Text en © The Author(s) 2021 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 Zhou, Huanjiao Jenny Qin, Lingfeng Jiang, Quan Murray, Katie N. Zhang, Haifeng Li, Busu Lin, Qun Graham, Morven Liu, Xinran Grutzendler, Jaime Min, Wang Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model |
title | Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model |
title_full | Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model |
title_fullStr | Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model |
title_full_unstemmed | Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model |
title_short | Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model |
title_sort | caveolae-mediated tie2 signaling contributes to ccm pathogenesis in a brain endothelial cell-specific pdcd10-deficient mouse model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835246/ https://www.ncbi.nlm.nih.gov/pubmed/33495460 http://dx.doi.org/10.1038/s41467-020-20774-0 |
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