Blood flow directs arterial-venous remodeling through Notch activation and endothelial cell migration

Arteries and veins are lined by arterial and venous endothelial cells (ECs), which are functionally distinct. During embryonic development, vascular remodeling transforms some arteries into veins. Arterial and venous embryonic ECs have the plasticity to transdifferentiate into each other, suggesting that the transformation of arteries to veins may be accompanied by transdifferentiation of ECs. Here, we show that transformation of arterial intersegmental vessels (aISVs) into veins occurs without trans-differentiation, by the displacement of arterial ECs by venous ECs, and requires normal blood flow. At the same time, the establishment of blood flow prevents neighboring aISVs from transforming into veins via the upregulation of Notch signaling in these aISVs. We propose that through these two processes, blood flow facilitates the transformation of the all-arterial trunk vasculature into a functional vascular network with near equal numbers of arteries and veins.