Abstract
The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity.
Highlights
It has become increasingly evident that disrupted lymphatic endothelial cells (LECs) junctions are potentially associated with various diseases, including lymphatic leakage present in chylothorax and lymphedema, metabolic syndrome, and impaired immune surveillance (Cifarelli and Eichmann, 2019; Jiang et al, 2019; Xiao et al, 2019; Norden and Kume, 2020; Zhang et al, 2020)
The recent seminal studies summarized in this review provide compelling evidence that RhoA/Rho-associated protein kinase (ROCK) signaling regulates LEC junction integrity in different vascular beds (Zhang et al, 2018; Hisano et al, 2019; Frye et al, 2020; Norden et al, 2020) (Table 1, Figure 2)
LECs are known to have the ability to undergo endothelial-to-mesenchymal transition (EndMT) by acquiring a mesenchymal cell phenotype, including loss of cell-cell junctions (Ichise et al, 2014; Dejana et al, 2017; Yoshimatsu et al, 2020). Another recent study demonstrates that as a non-Smad pathway, RhoA/ROCK signaling participates in TGF-β-induced EndMT of human dermal LECs in vitro (Yoshimatsu et al, 2020). This observation reinforces the importance of RhoA/ROCK activity in the regulation of LEC junction integrity
Summary
The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. We discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity
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