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Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling
Endothelial to mesenchymal transition (EndMT) is an important pathological change in many diseases. Semaphorin7A (Sema7A) has been reported to regulate nerve and vessel homeostasis, but its role in EndMT remains unclear. Here we investigate the effect of Sema7A on EndMT and the underlying mechanism....
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442651/ https://www.ncbi.nlm.nih.gov/pubmed/32826874 http://dx.doi.org/10.1038/s41419-020-02818-x |
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author | Hong, Lei Li, Fengchan Tang, Chaojun Li, Ling Sun, Lili Li, Xiaoqiang Zhu, Li |
author_facet | Hong, Lei Li, Fengchan Tang, Chaojun Li, Ling Sun, Lili Li, Xiaoqiang Zhu, Li |
author_sort | Hong, Lei |
collection | PubMed |
description | Endothelial to mesenchymal transition (EndMT) is an important pathological change in many diseases. Semaphorin7A (Sema7A) has been reported to regulate nerve and vessel homeostasis, but its role in EndMT remains unclear. Here we investigate the effect of Sema7A on EndMT and the underlying mechanism. Sema7A-overexpressed human umbilical vein endothelial cells (Sema7A-HUVECs) were generated and showed lower levels of endothelial cell markers and higher levels of mesenchymal cell markers indicating the occurrence of EndMT. RNA-sequencing analysis showed a total of 1168 upregulated genes and 886 downregulated genes. Among them, most of the molecules associated with EndMT were upregulated in Sema7A-HUVECs. Mechanistically, Sema7A-HUVECs showed a higher TGF-β2 expression and activated TGF-β/Smad Signaling. Importantly, Sema7A overexpression upregulated activating transcription factor 3 (ATF3) that was found to selectively bind the promotor region of TGF-β2, but not TGF-β1, promoting TGF-β2 transcription, which was further confirmed by ATF3-siRNA knockdown approach. Blocking β1 integrin, a known Sema7A receptor, alleviated the expression of ATF3, TGF-β2, and EndMT in Sema7A-overexpressed HUVECs, implying a role of β1 integrin/ATF3/TGF-β2 axis in mediating Sema7A-induced EndMT. Using Sema7A-deficient mice and the partial carotid artery ligation (PCL) model, we showed that Sema7A deletion attenuated EndMT induced by blood flow disturbance in vivo. In conclusion, Sema7A promotes TGF-β2 secretion by upregulating transcription factor ATF3 in a β1 integrin-dependent manner, and thus facilitates EndMT through TGF/Smad signaling, implying Sema7A as a potential therapeutic target for EndMT-related vascular diseases. |
format | Online Article Text |
id | pubmed-7442651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74426512020-09-02 Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling Hong, Lei Li, Fengchan Tang, Chaojun Li, Ling Sun, Lili Li, Xiaoqiang Zhu, Li Cell Death Dis Article Endothelial to mesenchymal transition (EndMT) is an important pathological change in many diseases. Semaphorin7A (Sema7A) has been reported to regulate nerve and vessel homeostasis, but its role in EndMT remains unclear. Here we investigate the effect of Sema7A on EndMT and the underlying mechanism. Sema7A-overexpressed human umbilical vein endothelial cells (Sema7A-HUVECs) were generated and showed lower levels of endothelial cell markers and higher levels of mesenchymal cell markers indicating the occurrence of EndMT. RNA-sequencing analysis showed a total of 1168 upregulated genes and 886 downregulated genes. Among them, most of the molecules associated with EndMT were upregulated in Sema7A-HUVECs. Mechanistically, Sema7A-HUVECs showed a higher TGF-β2 expression and activated TGF-β/Smad Signaling. Importantly, Sema7A overexpression upregulated activating transcription factor 3 (ATF3) that was found to selectively bind the promotor region of TGF-β2, but not TGF-β1, promoting TGF-β2 transcription, which was further confirmed by ATF3-siRNA knockdown approach. Blocking β1 integrin, a known Sema7A receptor, alleviated the expression of ATF3, TGF-β2, and EndMT in Sema7A-overexpressed HUVECs, implying a role of β1 integrin/ATF3/TGF-β2 axis in mediating Sema7A-induced EndMT. Using Sema7A-deficient mice and the partial carotid artery ligation (PCL) model, we showed that Sema7A deletion attenuated EndMT induced by blood flow disturbance in vivo. In conclusion, Sema7A promotes TGF-β2 secretion by upregulating transcription factor ATF3 in a β1 integrin-dependent manner, and thus facilitates EndMT through TGF/Smad signaling, implying Sema7A as a potential therapeutic target for EndMT-related vascular diseases. Nature Publishing Group UK 2020-08-10 /pmc/articles/PMC7442651/ /pubmed/32826874 http://dx.doi.org/10.1038/s41419-020-02818-x Text en © The Author(s) 2020 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 Hong, Lei Li, Fengchan Tang, Chaojun Li, Ling Sun, Lili Li, Xiaoqiang Zhu, Li Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling |
title | Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling |
title_full | Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling |
title_fullStr | Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling |
title_full_unstemmed | Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling |
title_short | Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling |
title_sort | semaphorin 7a promotes endothelial to mesenchymal transition through atf3 mediated tgf-β2/smad signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442651/ https://www.ncbi.nlm.nih.gov/pubmed/32826874 http://dx.doi.org/10.1038/s41419-020-02818-x |
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