Abstract. The lymphatic vascular system is a network of blind-ended lymphatic capillaries which collect extracellular fluid, and larger collecting lymphatic vessels which transport the fluid back to blood circulation. The major functions of the lymphatic system are the maintenance of tissue fluid homeostasis, intestinal fat absorption and immune surveillance via importing antigens and antigen-presenting cells to lymph nodes. The maintenance and function of the lymphatic system is controlled by growth factor receptors expressed by lymphatic endothelial cells (LECs). Two major signaling pathways that regulate the quiescence and remodeling of the lymphatic vasculature are the angiopoietin/tyrosine kinase with Ig-like and EGF-like domains (Ang/Tie) signaling pathway and the vascular endothelial growth factor C/vascular endothelial growth factor receptor 3 (VEGF-C/VEGFR-3) signaling pathway. The phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) pathway downstream regulates a variety of cellular functions including cell metabolism, growth, proliferation, and survival. One of the downstream effectors of PI3K/Akt signaling pathway is the transcription factor forkhead box protein O1 (FoxO1), which is inhibited via the activation of PI3K/Akt pathway. FoxO1 has a crucial role in inhibiting the formation of new lymphatic vessels by repressing genes involved in the process under normal conditions. During stress and inflammation, PI3K/Akt pathway is deactivated leading to FoxO1 translocation into the nucleus and where it activates the genes involved in vascular remodeling and destabilization. Understanding the pathways and mechanisms related to lymphatic vessel quiescence and remodeling has therapeutic value in manipulation of lymphangiogenesis e.g. in lymphedema and other pathologies in which lymphatic function is reduced
