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Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1
AIMS: Formation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this proce...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208898/ https://www.ncbi.nlm.nih.gov/pubmed/29845518 http://dx.doi.org/10.1007/s10456-018-9625-6 |
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author | Brandt, Maarten M. van Dijk, Christian G. M. Chrifi, Ihsan Kool, Heleen M. Bürgisser, Petra E. Louzao-Martinez, Laura Pei, Jiayi Rottier, Robbert J. Verhaar, Marianne C. Duncker, Dirk J. Cheng, Caroline |
author_facet | Brandt, Maarten M. van Dijk, Christian G. M. Chrifi, Ihsan Kool, Heleen M. Bürgisser, Petra E. Louzao-Martinez, Laura Pei, Jiayi Rottier, Robbert J. Verhaar, Marianne C. Duncker, Dirk J. Cheng, Caroline |
author_sort | Brandt, Maarten M. |
collection | PubMed |
description | AIMS: Formation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this process and here we investigated the molecular mechanism by which endothelial loss of this receptor attenuates angiogenesis. METHODS AND RESULTS: Using short interference RNA-mediated loss-of-function assays, the function and mechanism of signaling via Fzd5 was studied in human endothelial cells (ECs). Our findings indicate that Fzd5 signaling promotes neovessel formation in vitro in a collagen matrix-based 3D co-culture of primary vascular cells. Silencing of Fzd5 reduced EC proliferation, as a result of G(0)/G(1) cell cycle arrest, and decreased cell migration. Furthermore, Fzd5 knockdown resulted in enhanced expression of the factors Angpt2 and Flt1, which are mainly known for their destabilizing effects on the vasculature. In Fzd5-silenced ECs, Angpt2 and Flt1 upregulation was induced by enhanced PKC signaling, without the involvement of canonical Wnt signaling, non-canonical Wnt/Ca(2+)-mediated activation of NFAT, and non-canonical Wnt/PCP-mediated activation of JNK. We demonstrated that PKC-induced transcription of Angpt2 and Flt1 involved the transcription factor Ets1. CONCLUSIONS: The current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and Angpt2. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10456-018-9625-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6208898 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-62088982018-11-09 Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1 Brandt, Maarten M. van Dijk, Christian G. M. Chrifi, Ihsan Kool, Heleen M. Bürgisser, Petra E. Louzao-Martinez, Laura Pei, Jiayi Rottier, Robbert J. Verhaar, Marianne C. Duncker, Dirk J. Cheng, Caroline Angiogenesis Original Paper AIMS: Formation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this process and here we investigated the molecular mechanism by which endothelial loss of this receptor attenuates angiogenesis. METHODS AND RESULTS: Using short interference RNA-mediated loss-of-function assays, the function and mechanism of signaling via Fzd5 was studied in human endothelial cells (ECs). Our findings indicate that Fzd5 signaling promotes neovessel formation in vitro in a collagen matrix-based 3D co-culture of primary vascular cells. Silencing of Fzd5 reduced EC proliferation, as a result of G(0)/G(1) cell cycle arrest, and decreased cell migration. Furthermore, Fzd5 knockdown resulted in enhanced expression of the factors Angpt2 and Flt1, which are mainly known for their destabilizing effects on the vasculature. In Fzd5-silenced ECs, Angpt2 and Flt1 upregulation was induced by enhanced PKC signaling, without the involvement of canonical Wnt signaling, non-canonical Wnt/Ca(2+)-mediated activation of NFAT, and non-canonical Wnt/PCP-mediated activation of JNK. We demonstrated that PKC-induced transcription of Angpt2 and Flt1 involved the transcription factor Ets1. CONCLUSIONS: The current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and Angpt2. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10456-018-9625-6) contains supplementary material, which is available to authorized users. Springer Netherlands 2018-05-29 2018 /pmc/articles/PMC6208898/ /pubmed/29845518 http://dx.doi.org/10.1007/s10456-018-9625-6 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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. |
spellingShingle | Original Paper Brandt, Maarten M. van Dijk, Christian G. M. Chrifi, Ihsan Kool, Heleen M. Bürgisser, Petra E. Louzao-Martinez, Laura Pei, Jiayi Rottier, Robbert J. Verhaar, Marianne C. Duncker, Dirk J. Cheng, Caroline Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1 |
title | Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1 |
title_full | Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1 |
title_fullStr | Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1 |
title_full_unstemmed | Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1 |
title_short | Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1 |
title_sort | endothelial loss of fzd5 stimulates pkc/ets1-mediated transcription of angpt2 and flt1 |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208898/ https://www.ncbi.nlm.nih.gov/pubmed/29845518 http://dx.doi.org/10.1007/s10456-018-9625-6 |
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