Modeling Mechanical Feedback Mechanisms in a Multiscale Sliding Filament Model of Lymphatic Muscle Pumping

Abstract

The lymphatic system maintains bodily fluid balance by returning interstitial fluid to the venous system. Flow can occur through a combination of extrinsic pumping, due to forces from surrounding tissues, and intrinsic pumping involving contractions of muscle in the lymphatic vessel walls. Lymph transport is important not only for fluid homeostasis, but also for immune function, as lymph is a carrier for immune cells. Lymphatic muscle cells exhibit cardiac-like phasic contractions to generate flow and smooth-muscle-like tonic contractions to regulate flow. Lymphatic vessels therefore act as both active pumps and conduits. Lymphatic vessels are sensitive to mechanical stimuli, including flow-induced shear stresses and pressure-induced vessel stretch. These forces modulate biochemical pathways, leading to changes in intracellular calcium and interaction with regulatory and contractile proteins. In a multiscale computational model of phasic and tonic contractions in lymphatic muscle coupled to a lumped-parameter model of lymphatic pumping, we tested different models of the mechanical feedback mechanisms exhibited by lymphatics in experiments. Models were validated using flow and pressure experiments not used in the models construction. The final model shows that with flow-induced shear stress modulation, there is a small change in flow rate but an increase in muscle efficiency. A better understanding of the mechanobiology of lymphatic contractions can help guide future lymphatic vessel experiments, providing a basis for developing better treatments for lymphatic dysfunction.