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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
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.
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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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