RESUMO
Contractions of lymphangions, i.e., the segment between two one-way lymphatic valves, generate the pressure gradients that propel lymph back to the circulation. Each lymphangion is comprised of an inner sheet of lymphatic endothelial cells circumscribed by one or more layers of lymphatic muscle cells (LMCs). Each contraction is produced by an LMC action potential (AP) that propagates via gap junctions along the lymphangion. Yet, electrical coupling within and between cell layers and the impact on AP waves is poorly understood. Here, we combine studies in rat and mouse lymphatic vessels with mathematical modeling to show that initiation of AP waves depends on high input resistance (low current drain), whereas propagation depends on morphology and sufficient LMC:LMC coupling. Simulations show that 1) myoendothelial coupling is insignificant to facilitate AP generation and sustain an experimentally measured cross-junctional potential difference of 25 mV, i.e., AP waves propagate along the LMC layer only; 2) LMC:LMC resistance is estimated around 2-10 MΩ but depends on vessel structure and cell-cell coupling, e.g., some degree of LMC overlap protects AP waves against LMC decoupling; 3) the propensity of AP wave initiation is highest around the valves, where the density of LMCs is low; and 4) a single pacemaker cell embedded in the LMC layer must be able to generate very large currents to overcome the current drain from the layer. However, the required current generation to initiate an AP wave is reduced upon stimulation of multiple adjacent LMCs. With stimulation of all LMCs, AP waves can also arise from heterogeneity in the electrical activity of LMCs. The findings advance our understanding of the electrical constraints that underlie initiation of APs in the LMC layer and make testable predictions about how morphology, LMC excitability, and LMC:LMC electrical coupling interact to determine the ability to initiate and propagate AP waves in small lymphatic vessels.
