In developing and regenerating tissue, new arteries can arise from pre-existing veins through a cell fate switch that is thought to be triggered by blood flow. But arteries and veins are defined by opposing transcriptional programs, and how vein cells overcome an inhibitory transcriptional state to convert to arteries remains a major outstanding question. Kristy Red-Horse and colleagues show that the vein-to-artery cell fate switch occurs surprisingly early, prior to blood flow, in a process that creates pre-specified arterial cells that form coronary arteries. By analysing the vein-to-artery cell fate switch at single-cell resolution, they reveal two unexpected features: first, that the vein-to-artery conversion is gradual and overlapping until a transcriptional threshold is reached forming pre-specified artery cells and second, that this arterial pre-specification threshold is actively inhibited by cell cycle activation induced by the vein-specifying transcription factor COUP-TF2.
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