Arterialization requires the timely suppression of cell growth

Article

关键词: NOTCH;    ANGIOGENESIS;    EXPRESSION;    DLL4;    REVEALS;    PATHWAY;    LIGAND;   

DOI  :  10.1038/s41586-020-3018-x

来源: SCIE

【 摘 要 】

The formation of arteries is thought to occur by the induction of a highly conserved arterial genetic programme in a subset ofvessels that will later experience an increase in oxygenated blood flow(1,2). The initial steps of arterial specification require both the VEGF and Notch signalling pathways(3-5). Here, we combine inducible genetic mosaics and transcriptomicsto modulate and define the function of these signalling pathways in cell proliferation, arteriovenous differentiation and mobilization. We showthat endothelial cells with high levels ofVEGF or Notch signalling are intrinsically biased to mobilize and form arteries; however, they are notgenetically 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 promotesthe incorporation of endothelial cells into arteries. Mosaic lineage-tracing studies showed that endothelial cellsthat 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 processthat precedes arterial mobilization and complete differentiation.

【 授权许可】

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