Characterising lymphatic muscle contractility and a study on measuring lymph node permeability

Abstract

The weakening of Lymphatic Muscle (LM) is an essential contributor to the lymphatic pump dysfunction underlying many forms of lymphedema (Olsewski, 2002). Unfortunately, there is an essential lack of understanding of the molecular and mechanical properties of the LM. Current therapies to ameliorate lymphedema are limited to promoting passive lymph transfer. Despite the pivotal role of the lymphatic system, there is little known about the specific mechanical properties of LM which has widely considered to be equivalent in function to Vascular Smooth Muscle (VSM). This can be attributed by their common functional characteristics (1) both are able to develop and sustain spontaneous tone mediated by vasodilators and vasoconstrictors, (2) both dilate in response to intrinsic and imposed flow mediated by shear-stress sensitivity, and (3) both express contractile proteins common to vascular smooth muscles. However, recent studies have shown that lymphatic muscles share similar molecular actin isoforms and myosin heavy chains found in cardiac muscles (Zawieja, 2003) indicating that LM have unique characteristics separate from those of VSM. In addition, studies on mesenteric lymphatic vessels reveal that the passive Length-Tension (L-T) and Force-Velocity (F-V) relationship are fundamentally unique. The LM has the ability to develop a 5 to 10 fold increases of active force during maximal activation compared to spontaneous contraction (Davis, 2007). Furthermore, the F-V relationship in LM has been revealed to be much higher than that of VSM. The F-V relationship defines the actomyosin cross-bridge cycling rate and essentially helps us quantify the molecular and chemo-molecular transduction process. The LM has the ability to contract over a wider range of diameters improving pumping and contractility. As has been suggested by other experimental results, the LM is involved in a dynamic reorganisation of both cytoskeletal components and contractile units, through actin-myosin disconnectivity and changes in parallel to serial force transition pathway. This ‘adaptive’ reorganization allows for larger length changes within the LM. The aim of this study is to develop a new multi-scale model to analyse contractile behaviour under physiological and pathophysiological conditions. This will provide us with a greater insight to the fundamental mechanical difference between LM and VSM and potentially provide new avenues for selective therapeutic target of the lymphatic vessels. Our initial model is developed by adapting the Huxley-Hai-Murphy cross-bridge model which allows us to represent contractile unit kinetics, investigate the effect of dynamic remodelling of ‘force transmission pathways’ in cells and identify the characteristics involved in this robust system that allows various Lymphatic vessel diameter adaptations to lymph flow and pressure changes at both a molecular and cellular level. This modelling allows us to determine the intrinsic differences that make the LM so unique. To achieve this, a series of both computational and experimental approaches have been developed, to allow us to characterise and describe the behaviour of lymphatic muscles in vivo.