The lymphatic system performs many vital transport functions in the body. In addition to transporting proteins, lipids, and other particles, the lymphatic vessels transport 4-8 liters of fluid per day from the tissues back into circulation. If fluid builds up in the tissues, it results in debilitating swelling and pain called edema.
Lymphatic vessels transport fluid against a pressure differential and often against the force of gravity. To accomplish this requires active pumping by the lymphatic vessels as well as contraction caused by the surrounding tissues. However, the mechanisms that regulate lymphatic pumping and lymphatic flow are not well understood.
The lymphatic endothelial cells (LEC), which line the interior of lymphatic vessels, are known to be sensitive to the mechanical forces they experience. These include fluid shear stress (FSS) caused by lymph flow, and circumferential stretch (CS) which varies as the vessels contract. We are studying the LEC response under mechanical forces simulating “normal” and “edemagenic” conditions, to illuminate the biochemical mechanisms by which the LEC modify contraction under these conditions. We aim to identify relevant regulation pathways that can lead to targeted intervention to prevent or reverse edema.
Our approach is to culture isolated cells in bioreactors which can apply FSS and/or CS at physiologically-relevant levels. A variety of techniques will be used, including microfluidic chips and custom shear/stretch bioreactors. Fluorescence imaging and other modalities will be used to measure the biochemical signals produced by LEC under different conditions. This will give an indication of which regulatory pathways are involved in LEC regulation of lymphatic pumping in health and edema.