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VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions
Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell–cell interactions. Multiple VEGF-A isoforms exist, but the biol...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142621/ https://www.ncbi.nlm.nih.gov/pubmed/24966171 http://dx.doi.org/10.1091/mbc.E14-05-0962 |
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author | Fearnley, Gareth W. Odell, Adam F. Latham, Antony M. Mughal, Nadeem A. Bruns, Alexander F. Burgoyne, Nicholas J. Homer-Vanniasinkam, Shervanthi Zachary, Ian C. Hollstein, Monica C. Wheatcroft, Stephen B. Ponnambalam, Sreenivasan |
author_facet | Fearnley, Gareth W. Odell, Adam F. Latham, Antony M. Mughal, Nadeem A. Bruns, Alexander F. Burgoyne, Nicholas J. Homer-Vanniasinkam, Shervanthi Zachary, Ian C. Hollstein, Monica C. Wheatcroft, Stephen B. Ponnambalam, Sreenivasan |
author_sort | Fearnley, Gareth W. |
collection | PubMed |
description | Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell–cell interactions. Multiple VEGF-A isoforms exist, but the biological significance of this is unclear. Here we analyzed VEGF-A isoform–specific stimulation of VCAM-1 gene expression, which controls endothelial–leukocyte interactions, and show that this is dependent on both ERK1/2 and activating transcription factor-2 (ATF-2). VEGF-A isoforms showed differential ERK1/2 and p38 MAPK phosphorylation kinetics. A key feature of VEGF-A isoform–specific ERK1/2 activation and nuclear translocation was increased phosphorylation of ATF-2 on threonine residue 71 (T71). Using reverse genetics, we showed ATF-2 to be functionally required for VEGF-A–stimulated endothelial VCAM-1 gene expression. ATF-2 knockdown blocked VEGF-A–stimulated VCAM-1 expression and endothelial–leukocyte interactions. ATF-2 was also required for other endothelial cell outputs, such as cell migration and tubulogenesis. In contrast, VCAM-1 was essential only for promoting endothelial–leukocyte interactions. This work presents a new paradigm for understanding how soluble growth factor isoforms program complex cellular outputs and responses by modulating signal transduction pathways. |
format | Online Article Text |
id | pubmed-4142621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-41426212014-10-30 VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions Fearnley, Gareth W. Odell, Adam F. Latham, Antony M. Mughal, Nadeem A. Bruns, Alexander F. Burgoyne, Nicholas J. Homer-Vanniasinkam, Shervanthi Zachary, Ian C. Hollstein, Monica C. Wheatcroft, Stephen B. Ponnambalam, Sreenivasan Mol Biol Cell Articles Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell–cell interactions. Multiple VEGF-A isoforms exist, but the biological significance of this is unclear. Here we analyzed VEGF-A isoform–specific stimulation of VCAM-1 gene expression, which controls endothelial–leukocyte interactions, and show that this is dependent on both ERK1/2 and activating transcription factor-2 (ATF-2). VEGF-A isoforms showed differential ERK1/2 and p38 MAPK phosphorylation kinetics. A key feature of VEGF-A isoform–specific ERK1/2 activation and nuclear translocation was increased phosphorylation of ATF-2 on threonine residue 71 (T71). Using reverse genetics, we showed ATF-2 to be functionally required for VEGF-A–stimulated endothelial VCAM-1 gene expression. ATF-2 knockdown blocked VEGF-A–stimulated VCAM-1 expression and endothelial–leukocyte interactions. ATF-2 was also required for other endothelial cell outputs, such as cell migration and tubulogenesis. In contrast, VCAM-1 was essential only for promoting endothelial–leukocyte interactions. This work presents a new paradigm for understanding how soluble growth factor isoforms program complex cellular outputs and responses by modulating signal transduction pathways. The American Society for Cell Biology 2014-08-15 /pmc/articles/PMC4142621/ /pubmed/24966171 http://dx.doi.org/10.1091/mbc.E14-05-0962 Text en © 2014 Fearnley et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Fearnley, Gareth W. Odell, Adam F. Latham, Antony M. Mughal, Nadeem A. Bruns, Alexander F. Burgoyne, Nicholas J. Homer-Vanniasinkam, Shervanthi Zachary, Ian C. Hollstein, Monica C. Wheatcroft, Stephen B. Ponnambalam, Sreenivasan VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions |
title | VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions |
title_full | VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions |
title_fullStr | VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions |
title_full_unstemmed | VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions |
title_short | VEGF-A isoforms differentially regulate ATF-2–dependent VCAM-1 gene expression and endothelial–leukocyte interactions |
title_sort | vegf-a isoforms differentially regulate atf-2–dependent vcam-1 gene expression and endothelial–leukocyte interactions |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142621/ https://www.ncbi.nlm.nih.gov/pubmed/24966171 http://dx.doi.org/10.1091/mbc.E14-05-0962 |
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