Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

Abstract

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

Keywords: lymphatic development; lymphatic endothelial cell; lymphatic function; lymphatics; mechanical forces; mechanosensation; mechanotransduction; signaling pathways.

Figure 1

Cellular and molecular mechanisms involved in the separation of the blood and lymphatic vessel systems in mice. (A,B) Overview of the separation of the cardinal vein and the lymph sac with the formation of the lymphovenous valve in parallel with the platelet-dependent activation of the C-type lectin-like receptor 2 (CLEC-2)/spleen tyrosine kinase (SYK)/SH2-domain-containing leukocyte protein of 76 kDa (SLP-76)/phospholipase C gamma 2 (PLCγ2) pathway. (C) The CLEC-2/SYK/SLP-76/PLCγ2 pathway in platelets recognizing podoplanin (PDPN) expressed on the surface of lymphatic endothelial cells (LECs) is critical for the proper separation of the two circulatory systems.

Figure 2

Flow patterns in the lymphatic system. (A) LECs in branches are exposed to disturbed flow patterns with higher shear stress even before the establishment of intraluminal valves. (B) Flow becomes disturbed at the lymphatic valves of mature collecting lymphatic vessels. Valve-forming LECs and luminal LECs surrounding lymphatic valves are also exposed to disturbed flow, while LECs at other sites than branches, valves, and curvatures are exposed to a more laminar flow.

Figure 3

A schematic overview of the currently known mechanosensory and mechanotransduction molecular pathways in LECs. Lines represent direct connections between molecules, such as regulation of transcription, complex formation, direct activation, or inactivation. Dashed lines represent an indirect connection. Dotted lines represent assumed or still unclear connections.