Molecular Mechanisms Driving Lymphedema and Other Lymphatic Anomalies

Lymphatic vasculature regulates fluid homeostasis by absorbing interstitial fluid and returning it to blood. Lymphatic vasculature is also critical for lipid absorption and inflammatory response. Lymphatic vasculature is composed of lymphatic capillaries, collecting lymphatic vessels, lymphatic valves, and lymphovenous valves. Defects in any of these structures could lead to lymphatic anomalies such as lymphedema, cystic lymphatic malformation, and Gorham-Stout disease. Basic research has led to a deeper understanding of the stepwise development of the lymphatic vasculature. VEGF-C and shear stress signaling pathways have evolved as critical regulators of lymphatic vascular development. Loss-of-function and gain-of-function mutations in genes that are involved in these signaling pathways are associated with lymphatic anomalies. Importantly, drugs that target these molecules are showing outstanding efficacy in treating certain lymphatic anomalies. In this article, we summarize these exciting developments and highlight the future challenges.