(577c) Molecular And Biophysical Regulators Of Lymphatic Transport

Although the lymphatic system plays critical roles in tissue fluid balance, lipid transport, and immune cell trafficking, the active regulation of its drainage function, particularly in lymphatic capillaries, is poorly understood. Here we present in vitro and in vivo studies that reveal how lymphatic endothelial cells (LECs) actively regulate their function. In vivo, we explore how lipid transporters and diet affect lymphatic function in a series of transgenic mouse models, and show that dyslipidemia decreases lymphatic function and increases susceptibility to lymphedema. In vitro, we explore functional-adaptive responses of lymphatic endothelium to shear stress, which we propose is an indicator of function (i.e., high shear stress during acute inflammation, when lymph drains >10 times more lymph than normal, and low shear stress in lymphedema due to blocked lymphatic vessels). Specifically, LECs respond to shear stress by upregulating fluid and solute transporters, increasing their permeability, altering many lipid metabolites, and downregulating cell proliferation, among others. This indicates that during lymphedema or fluid stagnation, the potential for fluid and solute transport is drastically compromised, lipid metabolism is altered, and vessels become hyperplastic, which corresponds to in vivo observations. This work reveals key molecular regulators of lymphatic function and shows how shear stress, an indicator of function, affects those regulators, This work also supports the notion that lymphedema and obesity are intimately correlated