Abstract
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.
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