Arterialization requires the timely suppression of cell growth

Wen Luo, Irene Garcia-Gonzalez, Macarena Fernández-Chacón, Verónica Casquero-Garcia, Maria S. Sanchez-Muñoz, Severin Mühleder, Lourdes Garcia-Ortega, Jorge Andrade, Michael Potente and Rui Benedito ()
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Wen Luo: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Irene Garcia-Gonzalez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Macarena Fernández-Chacón: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Verónica Casquero-Garcia: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Maria S. Sanchez-Muñoz: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Severin Mühleder: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Lourdes Garcia-Ortega: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Jorge Andrade: Max Planck Institute for Heart and Lung Research
Michael Potente: Max Planck Institute for Heart and Lung Research
Rui Benedito: Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature, 2021, vol. 589, issue 7842, 437-441

Abstract: 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 flow1,2. The initial steps of arterial specification require both the VEGF and Notch signalling pathways3–5. 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.

Date: 2021
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DOI: 10.1038/s41586-020-3018-x

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