Molecular Regulation of Lymphatic Contractility

Abstract

The lymphatic system plays critical roles in body fluid and macromolecular homeostasis, lipid absorption, immune function, and metastasis. To accomplish these tasks, the lymphatics must move lymph and its contents from the interstitial space through the lymph vessels and nodes and into the great veins. Contrary to popular belief, lymph does not passively "drain" down this pathway, because the net pressure gradients oppose flow. Instead, the lymphatics must act as both the conduits that direct and regulate lymph flow and the pumps that generate the lymph flow. Thus, to regulate lymph transport and function, both lymphatic pumping and flow resistance must be controlled. Both of these processes occur via regulation of lymphatic muscle contractions, which are classically thought to occur via the interaction of cell calcium with regulatory and contractile proteins. However, our knowledge of this regulation of lymphatic contractile function is far from complete. In this chapter we review our understanding of the important molecular mechanisms, the calcium regulation, and the contractile/regulatory proteins that control lymphatic contractions. A better understanding of these mechanisms could provide the basis for the development of better diagnostic and treatment modalities for lymphatic dysfunction. While progress has been made in our understanding of the molecular biology of lymphangiogenesis as a result of the development of potential lymphangiogenic therapeutic targets, there are currently no therapeutic agents that specifically modulate lymphatic pump function and lymph flow via lymphatic muscle. However, their development will not be possible until the molecular basis of lymphatic contractility is more fully understood.

Independent and interactive effects of preload and afterload on the pump function of the isolated lymphangion

“…Our results, combined with previous work from multiple laboratories (29,36), suggest that lymphangion contractile function is modulated by the same four primary determinants of left ventricular function (37): preload, afterload, contraction FREQ, and inotropic state. Here, the term "inotropy" is used in a conservative sense that is consistent with the cardiac literature (rather than the lymphatic literature) to refer to an increase in muscle contractility (including a leftward shift in the ESPVR) induced by an applied agonist.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…In comparison, LECs of the collecting lymphatic vessels, opted for fluid transport rather than drainage, are now seamlessly aligned with each other by more tight, zipper-like junctions and ensheathed with the basement membranes and pericytes/smooth muscle cells that propel drained lymph fluids back to recirculation (Baluk et al 2007). Like the veins, collecting lymphatic vessels and ducts are equipped with bileaflet secondary valves to prevent retrograde flow of the lymph, and optimal lymph flow is effectively controlled by multiple factors including lymphatic muscle contractions (Dougherty et al 2008;Muthuchamy and Zawieja 2008). In addition to the tissue fluid homeostasis, the lymphatic system serves as a conduit for trafficking of lymphocytes and antigenpresenting cells to regional lymph nodes, where the immune system encounters pathogens, microbes, and other immune elicitors.…”

Estimation of the Pressure Drop Required for Lymph Flow through Initial Lymphatic Networks

“…24,26 The mesentery tissue has historically been used to study initial lymphatic vessel structure and function [27][28][29] and is also the most commonly used tissue for investigating contractile mechanisms in collecting lymphatic vessels. 2,3,[5][6][7][8] While future studies will be needed to identify whether tissue-specific geometries might influence the pressure drop requirement, it is logical to speculate that our estimates can be generalized to any branched network.…”

“…[2][3][4][5][6][7][8] In contrast to collecting lymphatics, initial lymphatic vessels are not wrapped in smooth muscle. With just a single endothelial layer, initial lymphatic function is considered to be passive and remains less understood.…”