School of Mathematics and Statistics, University of Sydney, Sydney, Australia.
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
J Gen Physiol. 2023 Dec 4;155(12). doi: 10.1085/jgp.202313355. Epub 2023 Oct 18.
Lymphatic system defects are involved in a wide range of diseases, including obesity, cardiovascular disease, and neurological disorders, such as Alzheimer's disease. Fluid return through the lymphatic vascular system is primarily provided by contractions of muscle cells in the walls of lymphatic vessels, which are in turn driven by electrochemical oscillations that cause rhythmic action potentials and associated surges in intracellular calcium ion concentration. There is an 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, thus both driving the action potentials. This extension results from modifications to the model's description of the IP3 receptor, a key C-clock mechanism. The synchronised dual-driving clock behaviour enables the model to match IP3 receptor knock-out data, thus resolving an issue with previous models. We also use phase-plane analysis to explain the mechanisms of coupling of the dual clocks. The model has the potential to help determine mechanisms and find targets for pharmacological treatment of some causes of lymphoedema.
淋巴系统缺陷与多种疾病有关，包括肥胖、心血管疾病和神经紊乱，如阿尔茨海默病。液体通过淋巴血管系统的回流主要由淋巴管壁的肌细胞收缩提供，而肌细胞的收缩又由电化学振荡驱动，引起有节奏的动作电位和细胞内钙离子浓度的相关激增。对于这些反复发生的事件涉及的机制，人们还不完全了解，这限制了针对功能障碍的药物治疗的发展。此前，我们提出了一个模型，其中细胞膜电位的自主振荡（M-时钟）驱动钙离子浓度的被动振荡（C-时钟）。在本文中，为了更准确地模拟已知的潜在生理学，我们将该模型扩展到 M-时钟和 C-时钟振荡器都处于活跃状态但相互耦合的情况，从而同时驱动动作电位。这一扩展源于对 IP3 受体模型描述的修改，IP3 受体是 C-时钟机制的关键。同步双驱动时钟行为使模型能够匹配 IP3 受体敲除数据，从而解决了先前模型存在的问题。我们还使用相平面分析来解释双时钟的耦合机制。该模型有可能有助于确定机制，并找到治疗淋巴水肿某些病因的药物治疗靶点。
