Molecular mechanisms enhancing lymphatic valve formation

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Lymphedema is a chronic disease that is caused by a dysfunctional lymphatic vasculature, and can occur from either genetic mutations or physical damage. The disease affects 3-5 million people in the US alone, and the majority are cancer survivors who had lymph node removal surgery. There are no effective treatments for lymphedema, nor any prevention strategies. Symptoms include severely swollen tissues due to adipose tissue deposition and fibrosis, resulting in an impaired immune response and recurring infections in patients. Numerous studies have established that chronic lymph stasis begets lymphedema. Impaired lymph flow in mice causes the regression of lymphatic valves because constant flow-mediated signals are required for the formation and ongoing maintenance of lymphatic valve leaflets. Further, forward lymph flow is maintained only by regularly spaced intraluminal valves derived from lymphatic endothelial cells (LEC). Lymphangiography of human patients with either congenital or acquired lymphedema is characterized by retrograde lymph flow, which strongly implicates defective or regressing lymphatic valves as a causative factor. Thus, a significant unmet need is to prevent lymphatic valve regression and/or stimulate lymphatic valve formation to treat lymphedema. Surprisingly little is known about how valve-forming genes are activated in response to fluid shear stress. We have identified the first transcription factor that acts as a repressor of lymphatic valve formation, Foxo1, and show that genetic deletion of Foxo1 from LEC increases the number of lymphatic valves significantly. Our data are the first to show that the ablation of any gene is capable of increasing the number of morphologically normal lymphatic valves. Thus, inhibitors of the Foxo1 pathway represent highly valuable pharmacologic targets to enhance valve formation. Our central hypothesis is that deletion of Foxo1 will increase the number of lymphatic valves by upregulating known valve-forming genes and will restore valve function in an animal model of lymphedema. This hypothesis will be tested by the following three aims: Aim 1 will determine the mechanisms by which loss of Foxo1 enhances lymphatic valve formation, Aim 2 will identify Foxo1-associated signaling pathways that increase lymphatic valve formation, and Aim 3 will  analyze the function of lymphatic valves in healthy and lymphedematous mice lacking Foxo1. It is highly anticipated that these aims will provide novel insights into the role of Foxo1 in regulating valve formation and function, which will ultimately lead to the identification of a druggable target and innovative therapy to treat patients with lymphedema by augmenting valve growth and function.