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The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms

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Title: The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms
Authors: Yuanyuan Zhang, Yumeng Zhang, Evelyn Hutterer, Sara Hultin, Otto Bergman, Solrun Kolbeinsdottir, Hong Jin, Maria J. Forteza, Daniel F. J. Ketelhuth, Joy Roy, Ulf Hedin, Martin Enge, Ljubica Matic, Per Eriksson, Lars Holmgren
Source: Nat Cardiovasc Res
Publisher Information: Springer Science and Business Media LLC, 2023.
Publication Year: 2023
Subject Terms: Male, 0301 basic medicine, Mechanotransduction, Cadherins/metabolism, Endothelial Cells/metabolism, Inbred C57BL, Mechanotransduction, Cellular, Abdominal/metabolism, Article, Mice, 03 medical and health sciences, Antigens, CD, Human Umbilical Vein Endothelial Cells, Animals, Humans, Aorta, Abdominal, Antigens, Human Umbilical Vein Endothelial Cells/metabolism, Aorta, Actin Cytoskeleton/metabolism, 0303 health sciences, Aortitis, Animal, CD/metabolism, Endothelial Cells, Aortitis/pathology, Cadherins, Actins, Aortic Aneurysm, Mice, Inbred C57BL, Disease Models, Animal, Actin Cytoskeleton, Angiomotins, Actins/metabolism, Disease Models, Cellular, Aortic Aneurysm, Abdominal
Description: Endothelial cells respond to mechanical forces exerted by blood flow. Endothelial cell–cell junctions and the sites of endothelial adhesion to the matrix sense and transmit mechanical forces to the cellular cytoskeleton. Here we show that the scaffold protein AmotL2 connects junctional VE-cadherin and actin filaments to the nuclear lamina. AmotL2 is essential for the formation of radial actin filaments and the alignment of endothelial cells, and, in its absence, nuclear integrity and positioning are altered. Molecular analysis demonstrated that VE-cadherin binds to AmotL2 and actin, resulting in a cascade that transmits extracellular mechanical signals to the nuclear membrane. Furthermore, the endothelial deficit of AmotL2 in mice fed normal diet provoked a pro-inflammatory response and abdominal aortic aneurysms (AAAs). Transcriptome analysis of human AAA samples revealed a negative correlation between AmotL2 and inflammation of the aortic intima. These findings offer insight into the link between junctional mechanotransduction and vascular disease.
Document Type: Article
Other literature type
Language: English
ISSN: 2731-0590
DOI: 10.1038/s44161-023-00298-8
Access URL: https://pubmed.ncbi.nlm.nih.gov/39195920
https://portal.findresearcher.sdu.dk/da/publications/550400fe-623e-4994-be6f-3d2a0b7ea487
https://doi.org/10.1038/s44161-023-00298-8
Rights: CC BY
URL: http://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/ (http://creativecommons.org/licenses/by/4.0/) .
Accession Number: edsair.doi.dedup.....917e93e83554dcf03570fa3453af59b7
Database: OpenAIRE
Description
Abstract:Endothelial cells respond to mechanical forces exerted by blood flow. Endothelial cell–cell junctions and the sites of endothelial adhesion to the matrix sense and transmit mechanical forces to the cellular cytoskeleton. Here we show that the scaffold protein AmotL2 connects junctional VE-cadherin and actin filaments to the nuclear lamina. AmotL2 is essential for the formation of radial actin filaments and the alignment of endothelial cells, and, in its absence, nuclear integrity and positioning are altered. Molecular analysis demonstrated that VE-cadherin binds to AmotL2 and actin, resulting in a cascade that transmits extracellular mechanical signals to the nuclear membrane. Furthermore, the endothelial deficit of AmotL2 in mice fed normal diet provoked a pro-inflammatory response and abdominal aortic aneurysms (AAAs). Transcriptome analysis of human AAA samples revealed a negative correlation between AmotL2 and inflammation of the aortic intima. These findings offer insight into the link between junctional mechanotransduction and vascular disease.
ISSN:27310590
DOI:10.1038/s44161-023-00298-8