Extended Data Fig. 10: Models for the regulation of arterialization by Notch.

The initial model used to describe arterialization was based on the assumption that an increase in pulsatile and oxygenated blood flow induces the direct differentiation and development of arterial vessels. The current model is based on the evidence that pre-arterial capillary ECs have higher Notch–RBPJ activity and higher expression of arterial genes. This model assumes that arterial fate is determined before the increase in arterial blood flow, through the direct induction of arterial gene expression via the Notch–RBPJ transcriptional complex. Here, we propose a model in which Notch–RBPJ suppresses MYC-dependent cell cycle or biosynthetic activity, rendering ECs more permissive to the adoption of an arterial phenotype without the need for Notch-dependent genetic pre-determination or differentiation. This model is supported by the observed phenotypic and transcriptomic outcomes in several mouse mutant models.