The lymphatic vessels’ winning philosophy: different challenges, tailored solutions

Abstract

The nature and function of the lymphatic vessels were correctly described for the first time by the Scottish anatomist and physician William Hunter (1718–1783) who proposed that the lymphatics were not ‘continuations from arteries, but a particular system of vessels by themselves’ and that lymph was formed by the absorption of fluid from the tissues into peripheral lymphatics (Hunter, 1762). Nowadays we know that the system originates with initial lymphatics, which drain fluid, particulates and cells from the extracellular space. The newly formed lymph is subsequently discharged into fewer and larger collecting lymphatics that transport the lymph back to the venous blood stream by means of well-synchronized contractions of the smooth muscle cells in their vessel wall. Much emphasis has recently been placed on the actual function of the lymphatic system, that not only controls tissue fluid homeostasis, but also: (a) maintains plasma volume constant, contributing to the regulation of arterial pressure and cardiovascular function; (b) returns leukocytes and cells, including tumoural ones, to the blood stream, thus contributing to host immune defence in lymph nodes; (c) may serve, particularly in some species, as a reservoir for extracellular fluid. What clearly emerged since their first systematic description is the extreme heterogeneity of the lymphatic structures, a specific characteristic of this vascular network that still makes it very difficult to deepen our knowledge of the physiology and patho-physiology of many lymphatic districts. Indeed, vessel shape, size and complexity is extremely variable from tissue to tissue. It has been clearly shown that this variability reflects various factors such as the specific microanatomy, the mechanical behaviour and, additionally and most importantly from the functional standpoint, the specific drainage requirements of the tissue (Aukland & Reed, 1993). The elegant study by Nepiyushchikh et al. in a recent issue of The Journal of Physiology (Nepiyushchikh et al. 2011), by looking deeper into the core mechanism of lymphatic contractility, introduces an additional degree of complexity into the already quite intricate frame and extends our knowledge about the contractile features of the lymphatic smooth muscle cells. The results reveal that the same contractile apparatus, i.e. the phosphorylation of myosin light chain 20 (MLC20), is exploited in a quite different manner in proximal collecting lymphatics such as the thoracic duct or the cervical lymphatics, compared to distal mesenteric lymphatics (Gashev et al. 2004). Indeed, inhibition of this contractile machinery more profoundly impairs muscle tone and contractile frequency in the thoracic duct than in cervical lymphatics, while such a MLC20 phosphorylation dependence was not observed in distal mesenteric vessels (Wang et al. 2009). Muscle tone and phasic contractile activity are also differently regulated: when the MLC20 phosphorylation pathway is highly expressed, as in thoracic duct and, to a lesser extent, in cervical lymphatics, the tonic activity prevails over the phasic one. Conversely, if the percentage MLC20 phosphorylation is low as in mesenteric lymphatics (Wang et al. 2009), the phasic activity prevails. Therefore, when coupled to the results of a previous study from the same group showing that the contractile mechanism of lymphangions in the wall of collecting lymphatics differs from that encountered in blood vessels (Muthuchamy et al. 2003), the study by Nepiyushchikh et al. reveals that function-dependent specifically tailored contractile machineries had developed in vascular smooth muscle cells. In blood vessels, blood flow is guaranteed by the cardiac pump and smooth muscle cell contraction modulates downstream tissue perfusion and upstream and/or downstream perfusion pressures. In the lymphatics, whose muscle cells posses both vascular and cardiac muscle contractile elements, contraction of smooth muscle cells is meant to sustain centripetal lymph progression against an adverse pressure gradient and extremely variable flow resistance. Each vessel is then equipped with a contractile apparatus to best exploit its function. The existence of differently regulated contractile machinery between distal mesenteric vessels and more proximal ones and even between differing proximal vessels is a significant example of how the lymphatic structures form an extremely sophisticated system able to separately adjust contraction force and frequency to cope with anatomical variability, functional flow requirements, and biodynamic flow transport properties.