Our working model of an exquisite negative feedback control mechanism among the major cell fate regulators, Notch, COUP-TFII, and Prox1. Our data presented in this study allow us to add 2 new regulatory components (bolded lines) to the previously proposed model^7,10  for endothelial cell fate specification. VEGF acts upstream of Notch, which regulates the arterial endothelial cell (EC) fate, and COUP-TFII governs venous EC fate. Prox1 interacts with COUP-TFII to specify LEC fate. Hey1 and Hey2 (Hey1/2) suppress Prox1 and COUP-TFII, which down-regulate VEGF receptors, VEGFR-2 and NP-1, to control VEGF activity.