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Arterialization requires the timely suppression of cell growth

Item Type:Article
Title:Arterialization requires the timely suppression of cell growth
Creators Name:Luo, W. and Garcia-Gonzalez, I. and Fernández-Chacón, M. and Casquero-Garcia, V. and Sanchez-Muñoz, M.S. and Mühleder, S. and Garcia-Ortega, L. and Andrade, J. and Potente, M. and Benedito, R.
Abstract:The formation of arteries is thought to occur by the induction of a highly conserved arterial genetic programme in a subset of vessels that will later experience an increase in oxygenated blood flow. The initial steps of arterial specification require both the VEGF and Notch signalling pathways. Here, we combine inducible genetic mosaics and transcriptomics to modulate and define the function of these signalling pathways in cell proliferation, arteriovenous differentiation and mobilization. We show that endothelial cells with high levels of VEGF or Notch signalling are intrinsically biased to mobilize and form arteries; however, they are not genetically pre-determined, and can also form veins. Mechanistically, we found that increased levels of VEGF and Notch signalling in pre-arterial capillaries suppresses MYC-dependent metabolic and cell-cycle activities, and promotes the incorporation of endothelial cells into arteries. Mosaic lineage-tracing studies showed that endothelial cells that lack the Notch–RBPJ transcriptional activator complex rarely form arteries; however, these cells regained the ability to form arteries when the function of MYC was suppressed. Thus, the development of arteries does not require the direct induction of a Notch-dependent arterial differentiation programme, but instead depends on the timely suppression of endothelial cell-cycle progression and metabolism, a process that precedes arterial mobilization and complete differentiation.
Keywords:Arteries, Calcium-Binding Proteins, Cell Differentiation, Cell Line, Cell Proliferation, Endothelial Cells, Extracellular Signal-Regulated MAP Kinases, Genetic Transcription, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Mosaicism, Mutation, Notch Receptors, Phenotype, Proto-Oncogene Proteins c-myc, Signal Transducing Adaptor Proteins, Signal Transduction, Time Factors, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelium, Veins, Animals, Mice
Publisher:Nature Publishing Group
Page Range:437-441
Date:21 January 2021
Additional Information:Copyright notice: Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
Official Publication:https://doi.org/10.1038/s41586-020-3018-x
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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