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Arterialization requires the timely suppression of cell growth

ABSTRACT: Arteries are thought to be formed through 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 VEGF and Notch signalling. Here, we combined inducible genetic mosaics and transcriptomics to modulate and define the function of these signalling pathways in cell proliferation, arteriovenous (AV) differentiation and mobilization. We observed that endothelial cells (ECs) with high VEGF or Notch signalling are intrinsically biased to mobilize and form arteries; nevertheless, they are not genetically pre-determined, and can also form veins. Mechanistically, we found that higher VEGF and Notch signalling in pre-arterial capillaries suppresses Myc-dependent metabolic and cell-cycle activities, promoting the incorporation of ECs in arteries. Mosaic lineage tracing studies revealed that ECs completely lacking the Notch-Rbpj transcriptional activator complex rarely form arteries; however, these cells regained the ability to form arteries when Myc function was suppressed. Thus, arterial development does not require the direct induction of a Notch-dependent arterial differentiation programme, but rather the timely suppression of endothelial cell-cycle progression and metabolism, a process preceding arterial mobilization and complete differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE158731 | GEO | 2020/09/30

REPOSITORIES: GEO

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Project description:Atherosclerotic plaques tend to form in the major arteries at certain predictable locations. As these arteries vary in atherosusceptibility, inter-arterial differences in endothelial cell (EC) biology are of considerable interest. To explore the origin of differences observed between typical atheroprone and atheroresistant arteries, we used DNA microarrays to compare gene expression profiles of harvested porcine coronary (CECs) and iliac (IECs) artery ECs grown in static culture out to passage four. Fewer differences were observed between the transcriptional profiles of CECs and IECs in culture compared to in vivo, suggesting that most differences observed in vivo were due to distinct environmental cues in the two arteries. One-class significance of microarrays revealed that most in vivo interarterial differences disappeared in culture, as fold differences after passaging were not significant for 85% of genes identified as differentially expressed in vivo at a 5% false discovery rate. However, the three homeobox genes HOXA9, HOXA10, and HOXD3 remained under-expressed in coronary endothelium for all passages by at least 9, 8, and 2-fold, respectively. Continued differential expression despite removal from the in vivo environment suggests that primarily heritable or epigenetic mechanism(s) influence transcription of these three genes. Quantitative real-time polymerase chain reaction confirmed expression ratios for seven genes associated with atherogenesis and over- or under-expressed by 3-fold in CECs relative to IECs. The present study provides evidence that both local environment and vascular bed origin modulate gene expression in arterial endothelium. The transcriptional differences observed here may provide new insights into pathways responsible for coronary artery susceptibility. Endothelial cells were freshly harvested from right coronary and iliac arteries from four pigs. Cells were cultured out to passage four. RNA was isolated after each passage and expression profiles were obtained using oligo microarrays.

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Arterialization requires the timely suppression of cell growth

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