Environmental and intrinsic modulations of venous differentiation

Endothelial cells in veins differ in morphology, function and gene expression from those in arteries and lymphatics. Understanding how venous and arterial identities are induced during development is required to understand how arterio-venous malformations occur, and to improve the outcome of vein grafts in surgery by promoting arterialization of veins. To identify factors that promote venous endothelial cell fate in vivo, we isolated veins from quail embryos, at different developmental stages, that were grafted into the coelom of chick embryos. Endothelial cells migrated out from the grafted vein and their colonization of host veins and/or arteries was quantified. We show that venous fate is promoted by sympathetic vessel innervation at embryonic day 11. Removal of sympathetic innervation decreased vein colonization, while norepinephrine enhanced venous colonization. BMP treatment or inhibition of ERK enhanced venous fate, revealing environmental neurotransmitter and BMP signaling and intrinsic ERK inhibition as actors in venous fate acquisition. We also identify the BMP antagonist Noggin as a potent mediator of venous arterialization.