A dual-clock-driven model emulating the effects of either Ano1 or IP₃R knock-out on lymphatic muscle cell pace-making

ABSTRACT Lymphoedema, a common dysfunction of the lymphatic system, results in fluid accumulating between cells. Fluid return through the lymphatic vascular system is primarily provided by contractions of muscle cells in the walls of lymphatic vessels, driven by electrochemical oscillations causing rhythmic action potentials and associated surges in intracellular calcium ion concentration. There is incomplete understanding of the mechanisms involved in these repeated events, restricting the development of pharmacological treatments for dysfunction. Previously, we proposed a model where autonomous oscillations in the membrane potential (M-clock) drove passive oscillations in the calcium concentration (C-clock). In this paper, to model more accurately what is known about the underlying physiology, we extend this model to the case where the M-clock and the C-clock oscillators are both active but coupled together, and thus both driving the action potentials. This extension results from modifications to the model for the IP 3 receptor, a key C-clock mechanism. The synchronized dual-driving clock behaviour enables the model to match IP 3 receptor knock-out data, resolving an issue with previous models. We also use phase-plane analysis to explain the mechanisms for the dual-clock coupling. The model has the potential to help determine mechanisms and find targets for pharmacological treatment of lymphoedema.