The functional and remodeling response of collecting lymphatic vessels to disruption of lymphatic drainage pathways

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Nelson, Tyler Scott
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The lymphatic system is composed of a network of vessels, nodes, and accessory organs that is present in most soft tissues of the body. The lymphatics play a vital role in maintaining tissue fluid homeostasis, trafficking immune cells from the periphery to the nodes, and transporting dietary lipids from the intestines to the blood stream. Unlike the blood vasculature, the lymphatic system does not have a central pump. Instead, transport is promoted by collecting lymphatic vessels that are composed of a series of contractile segments separated by one-way valves. When the normal function of the lymphatics is compromised a disease called lymphedema may develop, which is characterized by tissue fluid retention, fibrosis, and adipose accumulation. Unfortunately, lymphedema is a relatively common complication of cancer therapies that damage the lymphatic vasculature, such as lymph node dissections and radiation treatment. Despite being integral driver of lymphatic transport, relatively little is known about how collecting lymphatic function and remodeling may influence the development of lymphedema. This work demonstrates the development of novel near-infrared imaging methods with the ability to quantify and phenotype collecting lymphatic failure during lymphatic disease. These methods provide biological insight into the functional and remodeling response of the collecting lymphatic vessels to surgical disruption of lymphatic drainage pathways. Specifically, we demonstrate that diet-induced obesity adversely impacts collecting lymphatic contractility and pump function during lymphedema in a mouse model. Further, in a clinically relevant sheep model, we demonstrate that the uninjured vessel can compensate in vivo by altering its intrinsic functional response and structure; however, through this process, the collecting lymphatic muscle experiences increased oxidative stress due to increased contractility. The results of this work demonstrate that functional adaptations of the collecting lymphatic vessels may influence the development of lymphedema in a clinical setting.
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