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Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thro...

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Autores principales: Catar, Rusan, Moll, Guido, Hosp, Isa, Simon, Michele, Luecht, Christian, Zhao, Hongfan, Wu, Dashan, Chen, Lei, Kamhieh-Milz, Julian, Korybalska, Katarzyna, Zickler, Daniel, Witowski, Janusz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071415/
https://www.ncbi.nlm.nih.gov/pubmed/33920990
http://dx.doi.org/10.3390/cells10040910
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author Catar, Rusan
Moll, Guido
Hosp, Isa
Simon, Michele
Luecht, Christian
Zhao, Hongfan
Wu, Dashan
Chen, Lei
Kamhieh-Milz, Julian
Korybalska, Katarzyna
Zickler, Daniel
Witowski, Janusz
author_facet Catar, Rusan
Moll, Guido
Hosp, Isa
Simon, Michele
Luecht, Christian
Zhao, Hongfan
Wu, Dashan
Chen, Lei
Kamhieh-Milz, Julian
Korybalska, Katarzyna
Zickler, Daniel
Witowski, Janusz
author_sort Catar, Rusan
collection PubMed
description Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1–ERK1/2–AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis.
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spelling pubmed-80714152021-04-26 Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response Catar, Rusan Moll, Guido Hosp, Isa Simon, Michele Luecht, Christian Zhao, Hongfan Wu, Dashan Chen, Lei Kamhieh-Milz, Julian Korybalska, Katarzyna Zickler, Daniel Witowski, Janusz Cells Article Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1–ERK1/2–AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis. MDPI 2021-04-15 /pmc/articles/PMC8071415/ /pubmed/33920990 http://dx.doi.org/10.3390/cells10040910 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Catar, Rusan
Moll, Guido
Hosp, Isa
Simon, Michele
Luecht, Christian
Zhao, Hongfan
Wu, Dashan
Chen, Lei
Kamhieh-Milz, Julian
Korybalska, Katarzyna
Zickler, Daniel
Witowski, Janusz
Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response
title Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response
title_full Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response
title_fullStr Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response
title_full_unstemmed Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response
title_short Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response
title_sort transcriptional regulation of thrombin-induced endothelial vegf induction and proangiogenic response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071415/
https://www.ncbi.nlm.nih.gov/pubmed/33920990
http://dx.doi.org/10.3390/cells10040910
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