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RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations

BACKGROUND: The blood flow rate of brain arteriovenous malformations (bAVMs) is an important clinical characteristic closely associated with the hemorrhage risk and radiosurgery obliteration rate of bAVMs. However, the underlying molecular properties remain unclear. To identify potential key molecul...

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Autores principales: Huo, Ran, Fu, Weilun, Li, Hao, Jiao, Yuming, Yan, Zihan, Wang, Linjian, Wang, Jie, Wang, Shuo, Cao, Yong, Zhao, Jizong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645621/
https://www.ncbi.nlm.nih.gov/pubmed/31170876
http://dx.doi.org/10.1161/JAHA.119.012746
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author Huo, Ran
Fu, Weilun
Li, Hao
Jiao, Yuming
Yan, Zihan
Wang, Linjian
Wang, Jie
Wang, Shuo
Cao, Yong
Zhao, Jizong
author_facet Huo, Ran
Fu, Weilun
Li, Hao
Jiao, Yuming
Yan, Zihan
Wang, Linjian
Wang, Jie
Wang, Shuo
Cao, Yong
Zhao, Jizong
author_sort Huo, Ran
collection PubMed
description BACKGROUND: The blood flow rate of brain arteriovenous malformations (bAVMs) is an important clinical characteristic closely associated with the hemorrhage risk and radiosurgery obliteration rate of bAVMs. However, the underlying molecular properties remain unclear. To identify potential key molecules, signaling pathways, and vascular cell types involved, we compared gene expression profiles between bAVMs with high flow rates and low flow rates (LFR) and validated the functions of selected key molecules in vitro. METHODS AND RESULTS: We performed RNA‐sequencing analysis on 51 samples, including 14 high flow rate bAVMs and 37 LFR bAVMs. Functional pathway analysis was performed to identify potential signals influencing the flow rate phenotype of bAVMs. Candidate genes were investigated in bAVM specimens by immunohistochemical staining. Migration, tube formation, and proliferation assays were used to test the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells and human brain vascular smooth muscle cells. We identified 250 upregulated and 118 downregulated genes in LFR bAVMs compared with high flow rate bAVMs. Wnt signaling was activated in the LFR group via upregulation of FZD10 and MYOC. Immunohistochemical staining showed that vascular endothelial and smooth muscle cells of LFR bAVMs exhibited increased FZD10 and MYOC expression. Experimentally elevating these genes promoted human umbilical vein endothelial cells and migration and tube formation by activating canonical Wnt signaling in vitro. CONCLUSIONS: Our results suggest that canonical Wnt signaling mediated by FZD10 and MYOC is activated in vascular endothelial and smooth muscle cells in LFR bAVMs.
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spelling pubmed-66456212019-07-31 RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations Huo, Ran Fu, Weilun Li, Hao Jiao, Yuming Yan, Zihan Wang, Linjian Wang, Jie Wang, Shuo Cao, Yong Zhao, Jizong J Am Heart Assoc Original Research BACKGROUND: The blood flow rate of brain arteriovenous malformations (bAVMs) is an important clinical characteristic closely associated with the hemorrhage risk and radiosurgery obliteration rate of bAVMs. However, the underlying molecular properties remain unclear. To identify potential key molecules, signaling pathways, and vascular cell types involved, we compared gene expression profiles between bAVMs with high flow rates and low flow rates (LFR) and validated the functions of selected key molecules in vitro. METHODS AND RESULTS: We performed RNA‐sequencing analysis on 51 samples, including 14 high flow rate bAVMs and 37 LFR bAVMs. Functional pathway analysis was performed to identify potential signals influencing the flow rate phenotype of bAVMs. Candidate genes were investigated in bAVM specimens by immunohistochemical staining. Migration, tube formation, and proliferation assays were used to test the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells and human brain vascular smooth muscle cells. We identified 250 upregulated and 118 downregulated genes in LFR bAVMs compared with high flow rate bAVMs. Wnt signaling was activated in the LFR group via upregulation of FZD10 and MYOC. Immunohistochemical staining showed that vascular endothelial and smooth muscle cells of LFR bAVMs exhibited increased FZD10 and MYOC expression. Experimentally elevating these genes promoted human umbilical vein endothelial cells and migration and tube formation by activating canonical Wnt signaling in vitro. CONCLUSIONS: Our results suggest that canonical Wnt signaling mediated by FZD10 and MYOC is activated in vascular endothelial and smooth muscle cells in LFR bAVMs. John Wiley and Sons Inc. 2019-06-07 /pmc/articles/PMC6645621/ /pubmed/31170876 http://dx.doi.org/10.1161/JAHA.119.012746 Text en © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Huo, Ran
Fu, Weilun
Li, Hao
Jiao, Yuming
Yan, Zihan
Wang, Linjian
Wang, Jie
Wang, Shuo
Cao, Yong
Zhao, Jizong
RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations
title RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations
title_full RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations
title_fullStr RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations
title_full_unstemmed RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations
title_short RNA Sequencing Reveals the Activation of Wnt Signaling in Low Flow Rate Brain Arteriovenous Malformations
title_sort rna sequencing reveals the activation of wnt signaling in low flow rate brain arteriovenous malformations
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645621/
https://www.ncbi.nlm.nih.gov/pubmed/31170876
http://dx.doi.org/10.1161/JAHA.119.012746
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