Multi‐scale Modeling of Collecting Lymphatic Vessels: From Ion Channel Activity to Lymph Transport

Abstract

Exact physical, molecular and cellular mechanisms underlying the transport of the lymph within the lymphatic system is highly complicated, and for the most part is poorly understood. This proposed research outlines our recent effort in developing a multiscale computational model of collecting lymphatic vessel segments (lymphangions), in which the transport function at macroscale level can be analyzed by integrating underlying mechanisms at cellular and molecular levels. This outlined approach can provide a useful platform to study the function or dysfunction of the collecting lymphatic vessels in normal and diseased states, respectively. Detailed mathematical expressions of electrophysiological properties of major ionic channels, membrane currents and intracellular stores present in a single lymphatic smooth muscle cell (LSMC) has been derived from independent experimental studies in literature. The single LSMC model predicts the detailed dynamics of calcium and membrane potential at the whole cell level via integrating individual membrane and intracellular components. A model of the lymphangion wall is constructed via connecting LSMCs through the incorporation of homocellular gap junctions between the neighboring cells. This multicellular model has the potential to lay bare on complex intra‐ and intercellular electrical signaling and propagating ionic waves. The detailed electrophysiological model of the lymphangion wall is combined with a biomechanics and fluid dynamics model to form a mathematical model of a section of the collecting lymphatic vessel (i.e. a series of lymphangions separated by unidirectional valves). This model allows us to study the real‐time relationship between the changes in the diameter and pressure of the vessel segments and changes in the concentration of ionic species. The single LSMC model successfully predicts calcium and membrane current oscillations at physiological amplitude and frequencies without the presence of an agonist. The multicellular model suggests that the chloride current is the major contributor in synchronizing the LSMC spontaneous contractions within one lymphangion, while the presence of pressure‐sensitive channels accounts for anti‐phase contractions observed in neighboring lymphangions. This proposed model is a novel attempt that synergistically takes into account the biomechanics of the lymphatic vessel wall, fluid dynamics, and the electrophysiology of major ionic species in the cells constituting the lymphatic vessels.Support or Funding InformationSupported by National Institutes of Health grant HL121778