Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity

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.

Notch signalling in healthy and diseased vasculature

“…During the postnatal stages, Notch signalling is also important for the lymphatic system [ 36 ], and Notch serves a role in restricting VEGF-induced lymphatic endothelial sprouting [ 37 ]. The role of Notch in maintaining lymphatic EC junctional integrity has also been described [ 38 , 39 ].…”

Recent Progress in Lymphangioma

“…However, common LM may also occur in other organs containing lymphatic vessels, such as the chest wall, trunk, limbs and parenchymal organs (12). Common LM can be divided into three types: macrocystic LM (diameter > 1 cm), microcystic LM (diameter < 1 cm) and mixed cystic LM (13,14). Histologically, LM cysts may be vacant or filled with protein-rich fluid brimming with lymphocytes and macrophages (15)(16)(17).…”

Lymphatic Collecting Vessel: New Perspectives on Mechanisms of Contractile Regulation and Potential Lymphatic Contractile Pathways to Target in Obesity and Metabolic Diseases

“…Milroy disease specifically, is an autosomal dominant congenital form of lymphedema that is typically attributed to mutations within VEGFR3 ( Irrthum et al, 2000 ; Karkkainen et al, 2001 ; Schulte-Merker et al, 2011 ). The importance of VEGFC and VEGFR3 signaling in disease has been recently highlighted by Norden et al (2020) ( Norden and Kume, 2020 ). Although much is known about the role of VEGFR3 in lymphangiogenesis, less is understood regarding the role of VEGFR3 activation in physiological regulation in collecting lymphatic vessels.…”

“…Targeting the intestinal lacteals ( Bernier-Latmani et al, 2015 ; Nurmi et al, 2015 ) or the LEC-LEC junctions ( Zhang et al, 2018 ) in the lacteal hold promise as potential pharmacological targets in obesity. LEC junction regulation in metabolic disease has been reviewed elsewhere ( Zhang et al, 2018 ; Norden and Kume, 2021 ; Kataru et al, 2020 ).…”

“…The mechanisms by which obesity may interact with the gene pathways critical to lymphangiogenesis and lymphatic endothelial maintenance have been recently described (Norden and Kume, 2021;Ho and Srinivasan, 2020;Kataru et al, 2020). An examination of the effects of vasoactive molecules on lymphatic function and their respective pharmacological implications has also been recently discussed in the exhaustive review (Russell et al, 2021).…”