A multiscale sliding filament model of lymphatic muscle pumping

Christopher J Morris,James E Moore,David C Zawieja

doi:10.1007/s10237-021-01501-0

Christopher J Morris, James E Moore + Show 1 more

Open Access

https://doi.org/10.1007/s10237-021-01501-0

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Abstract

The lymphatics maintain fluid balance by returning interstitial fluid to veins via contraction/compression of vessel segments with check valves. Disruption of lymphatic pumping can result in a condition called lymphedema with interstitial fluid accumulation. Lymphedema treatments are often ineffective, which is partially attributable to insufficient understanding of specialized lymphatic muscle lining the vessels. This muscle exhibits cardiac-like phasic contractions and smooth muscle-like tonic contractions to generate and regulate flow. To understand the relationship between this sub-cellular contractile machinery and organ-level pumping, we have developed a multiscale computational model of phasic and tonic contractions in lymphatic muscle and coupled it to a lymphangion pumping model. Our model uses the sliding filament model (Huxley in Prog Biophys Biophys Chem 7:255–318, 1957) and its adaptation for smooth muscle (Mijailovich in Biophys J 79(5):2667–2681, 2000). Multiple structural arrangements of contractile components and viscoelastic elements were trialed but only one provided physiologic results. We then coupled this model with our previous lumped parameter model of the lymphangion to relate results to experiments. We show that the model produces similar pressure, diameter, and flow tracings to experiments on rat mesenteric lymphatics. This model provides the first estimates of lymphatic muscle contraction energetics and the ability to assess the potential effects of sub-cellular level phenomena such as calcium oscillations on lymphangion outflow. The maximum efficiency value predicted (40%) is at the upper end of estimates for other muscle types. Spontaneous calcium oscillations during diastole were found to increase outflow up to approximately 50% in the range of frequencies and amplitudes tested.

Highlights

Fluid homeostasis is maintained by the converging vessels of the lymphatic system that in humans return 4–8 L of interstitial fluid to the venous system in lymph nodes and at the subclavian veins
The mid-lymphangion pressure increased to a peak value of 0.21 cmH2O above the outlet (Fig. 4c) and reduced to 0.06 cmH2O below the inlet pressure to create a suction effect for diastolic filling hydrolysis to model the metabolic efficiency of lymphatic muscle and the useful energy imparted to the fluid (Fig. 4c)
We have developed a computer model of the subcellular mechanisms of lymphatic muscle contraction that, on coupling with a well-characterized macroscale model of lymphangion pumping, produces flow, diameter, and pressure traces similar to those from experiments on rat mesenteric lymphatics

Summary

Introduction

Fluid homeostasis is maintained by the converging vessels of the lymphatic system that in humans return 4–8 L of interstitial fluid to the venous system in lymph nodes and at the subclavian veins. Lymphatics lack a central pump equivalent to the heart, so fluid propulsion is achieved by a combination of active lymphatic contraction and external compression from surrounding tissues. The relative contributions of intrinsic contractions and external compression vary throughout the lymphatic tree. The initial lymphatic vessels, consisting of endothelial lining and basement membrane, do not actively contract in most tissue and species. These vessels lead to larger “collecting” lymphatic vessels, where active contractions often occur due to specialized lymphatic muscle cells (LMCs) in the wall. Vessel contractions are very nearly uniform in the segments between valves (called “lymphangions”), so peristalsis is not a relevant mechanism for active pumping. Lymph transport works against an adverse pressure gradient to remove fluid from low or subatmospheric pressures in the interstitium into and along lymphatics with higher positive pressures (Zweifach and Prather 1975, Hargens and Zawiefach 1977, Aukland & Reed 1993; Guyton et al 1971; Jamalian et al 2017)

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