FOXO1 represses lymphatic valve formation and maintenance via PRDM1.

Intraluminal lymphatic valves (LVs) contribute to the prevention of lymph backflow and maintain circulatory homeostasis. Several reports have investigated the molecular mechanisms which promote LV formation; however, the way in which they are suppressed is not completely clear. We show that the forkhead transcription factor FOXO1 is a suppressor of LV formation and maintenance in lymphatic endothelial cells. Oscillatory shear stress by bidirectional flow inactivates FOXO1 via Akt phosphorylation, resulting in the upregulation of a subset of LV-specific genes mediated by downregulation of a transcriptional repressor, PRDM1. Mice with an endothelial-specific Foxo1 deletion have an increase in LVs, and overexpression of Foxo1 in mice produces a decrease in LVs. Genetic reduction of PRDM1 rescues the decrease in LV by Foxo1 overexpression. In conclusion, FOXO1 plays a critical role in lymph flow homeostasis by preventing excess LV formation. This gene might be a therapeutic target for lymphatic circulatory abnormalities.