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WIREs Syst Biol Med
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Lymphatic vessels in health and disease

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Abstract The lymphatic vasculature plays vital roles in tissue fluid balance, immune defense, metabolism, and cancer metastasis. In adults, lymphatic vessel formation and remodeling occur primarily during inflammation, development of the corpus luteum, wound healing, and tumor growth. Unlike the blood circulation, where unidirectional flow is sustained by the pumping actions of the heart, pumping actions intrinsic to the lymphatic vessels themselves are important drivers of lymphatic flow. This review summarizes critical components that control lymphatic physiology. WIREs Syst Biol Med 2013, 5:111–124. doi: 10.1002/wsbm.1201 This article is categorized under: Physiology > Mammalian Physiology in Health and Disease

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Initial and collecting lymphatics. The lymphatic vessels of the ear of an athymic nude mouse are shown. LYVE‐1 (green) indicates the initial lymphatic vessels. α‐smooth muscle actin (SMA) (red) indicates the smooth muscle cells (SMCs) of the collecting lymphatic vessels and blood vessels. The circumferential α‐SMA staining pattern of the collecting lymphatic vessels is distinct from the more homogenous pattern of the blood vessels. CD31 (white) indicates all endothelial cells in the field and shows an intraluminal valve in the collecting lymphatic vessel.

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Components of lymphatic metastasis. In contrast to functional blood vessels that can be found throughout the tumor, functional lymphatic vessels are found in the margin of tumors. These tumor margin lymphatic vessels tend to be enlarged and have greater lymph flow compared to lymphatic vessels draining normal tissues. These functional lymphatics are penetrated by invading cancer cells, which travel to the draining lymph node (LN) where they evade the immune system and start to form a secondary metastatic tumor. Understanding the growth of the cancer cells in the LN is critical for the development of effective treatment for these metastatic lesions.

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Microarchitecture of the lymph node (LN). This simplified schematic of the LN highlights key structural features critical for the proper activation of an immune response. The adipose‐encased afferent collecting lymphatic vessels move antigen‐rich lymph into the subcapsular sinus. Fluid and small antigens can then filter into the LN cortex, where B cell follicles are found. Reticular fibers, bound by their associated fibroblastic reticular cells (FRCs) and specialized dendritic cells (DCs), traverse the cortex to rapidly bring antigen to the paracortical and medullary regions where T cells reside. High endothelial venules (HEVs) in the paracortical area bring naïve T cells into the node as well to interact with DCs. In the medulla, there are lymphatic vessels that drain the LN and collect fluid into the efferent lymphatic vessel.

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Lymphatic contraction. This illustration of the diastolic and systolic phases of an autonomous lymphatic contraction shows the nitric oxide (NO) dependency. In the diastolic phase, local NO release allows for the relaxation of the vessel wall and filling to occur. As the NO degrades, the vessel constricts, driving flow into the next lymphangion. It is hypothesized that the increase in flow and shear stress as a result of a contraction stimulates NO production, allowing the diastolic filling to occur. The spatial and temporal gradients of NO are critical to proper contraction function and are mediated by endothelial nitric oxide synthase (eNOS) in lymphatic endothelial cell (LECs).

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