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.

Neutrophil Interactions with the Lymphatic System

“…Emerging evidence suggests that neutrophils may also interact with the lymphatic system by regulating lymphangiogenesis (or growth of new lymphatic vessels) in inflamed tissues and lymph nodes during inflammation and cancer progression [3,95]. Recent studies have identified signals which promote the formation of the lymphatic vasculature [96,97]. Vascular endothelial growth factors, such as VEGF-A, VEGF-C and VEGF-D can induce LEC sprouting and proliferation.…”

Draining the Pleural Space: Lymphatic Vessels Facing the Most Challenging Task

“…In humans, the lymphatic system begins to develop between the 6th and 7th week of pregnancy, whereas in mice it appears around the embryonic day 10 (E10.0). The wellknown homeobox transcription factor Prox1 (Prospero homeobox 1) [75] and the growth factor VEGFC (Vascular endothelial growth factor C) [76] are typical LECs markers, playing a critical role in lymphatic vessels prenatal sprouting from embryonic veins and maturation [77,78]. Prox1 upregulates the expression of lymphatic-specific genes in LECs acting as a master regulatory gene leading to lymphatic commitment and maintenance [79,80].…”

Low Efficacy of Genetic Tests for the Diagnosis of Primary Lymphedema Prompts Novel Insights into the Underlying Molecular Pathways

“…Mechanical forces are proven to contribute to endothelial cell fate commitment, influencing LECs' shape and alignment. They promote sprouting, development, and maturation of the lymphatic network, and they coordinate lymphatic valve morphogenesis [99,100]. Many of the proposed candidate genes are linked to lymphatic valve morphogenesis (EFNB2, EMILIN1, GJA4, ITGA9, NFATC1, PECAM1, and PLXNA1) (see Supplementary Table S2).…”