The transcription factor FOXO1 orchestrates growth and maturation of lymphatics

Abstract

The lymphatic vascular system is a unidirectional vascular network connecting the extracellular space with the venous blood circulation. It is essential for accurate regulation of homeostasis, intestinal fat absorption and immune response. Accurate development and maturation of these vessels is indispensable for growth and survival of the organism. Increased lymphangiogenesis is a hallmark of many tumor entities, whereas decreased lymphatic function can lead to lymphedema. Previous work from our laboratory has revealed the function of the transcription factor Forkhead Box O1 (FOXO1) in blood endothelial cells as an inductor of quiescence. Using lymphendothelial cell-specific overexpression in vitro and in vivo, we investigate the function of FOXO1 in the development and maturation of the lymphatic vasculature. In vivo, FOXO1 overexpression resulted in a sparse lymphatic network, exhibiting reduced proliferation. In vitro, we demonstrated downregulation of many genes involved in lymphatic vessel maturation. In addition, FOXO1 appears to reduce MYC and mTORC1 signaling and thereby diverse metabolic pathways, such as lipid and sterol biosynthesis, which may explain reduced cell growth. This study reveals FOXO1 as a regulator of proliferation and maturation in the lymphatic vasculature. Our results demonstrate that proper development and maintenance of the lymphatic vascular network requires precise regulation of FOXO1, and alterations lead to defects in proliferation and maturation. Thus, FOXO1 might have a role in the pathogenesis of lymphatic diseases such as hereditary lymphedema and might evolve as an appealing target to treat these disorders.