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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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Detalles Bibliográficos
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
Descripción
Sumario: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.