Biomechanical control of lymphatic vessel physiology and functions

Abstract

The ever-growing research on lymphatic biology has clearly identified lymphatic vessels as key players that maintain human health through their functional roles in tissue fluid homeostasis, immunosurveillance, lipid metabolism and inflammation. It is therefore not surprising that the list of human diseases associated with lymphatic malfunctions has grown larger, including issues beyond lymphedema, a pathology traditionally associated with lymphatic drainage insufficiency. Thus, the discovery of factors and pathways that can promote optimal lymphatic functions may offer new therapeutic options. Accumulating evidence indicates that aside from biochemical factors, biomechanical signals also regulate lymphatic vessel expansion and functions postnatally. Here, we review how mechanical forces induced by fluid shear stress affect the behavior and functions of lymphatic vessels and the mechanisms lymphatic vessels employ to sense and transduce these mechanical cues into biological signals.

Keywords: biomechanical force; human diseases; lymphatic vessel; mechanosensing; mechanotransduction.

Fig. 1

Structure and function of the lymphatic system. A The lymphatic vasculature (green) forms part of the circulatory system. Fluid that extravasates from the blood capillary bed into the tissue interstitium is absorbed into initial lymphatics vessels and flows through larger collecting lymphatic vessels that actively transport lymph fluid into draining lymph nodes before returning into the venous system via the thoracic duct. B Interstitial fluid, macromolecules and immune cells leave the tissue interstitium to enter discontinuous button-like initial lymphatic vessels that lack a continuous basement membrane. Collecting lymphatic vessels have a continuous basement membrane, smooth muscle cell coverage to provide contractile activity to assist blood flow and intraluminal valves to prevent lymph backflow. Collecting LECs are organized into tight continuous zipper-like junctions and do not absorb fluid from surrounding tissues. C Initial lymphatic vessels are composed of overlapping LECs that allow interstitial components to enter the vessels when interstitial pressure is high. The overlapping cells also act as valves, preventing fluid from leaking out. Anchoring filaments connect LECs to the surrounding extracellular matrix and facilitate fluid, macromolecule and cell entry into initial lymphatic vessels. D The collecting lymphatic vessels are composed of several lymphangions that propagate lymph flow. Coordinated contraction/expansion of each lymphangion and opening/closing of intraluminal valves ensure efficient lymph transport. LEC lymphatic endothelial cell, BM basement membrane, SMC smooth muscle cell. Created with BioRender.com

Fig. 2

Fluid shear stress induced changes in lymphatics. A Effects of fluid shear stress on lymphatic vasculature and function. B Mechanosensory and mechanotransduction pathways in lymphatic endothelial cells. Lymphatic endothelial cells sense shear stress produced by interstitial fluid flow via 2 possible mechanisms. The mechanosensory complex, including PECAM, VE-cadherin, VEGFR2 and VEGFR3, senses fluid shear stress and activates the PI3K/Akt pathway, induces cytoskeleton reorganization and regulates YAP/TAZ signaling. In addition to effects on this complex, flow sensing leads to the activation of VEGFR3 phosphorylation via its ligand VEGF-C or interaction with β1 integrin and induces the downstream pathway activation mentioned above and the regulation of key genes, including the master transcription factors PROX-1, FOXC2, GATA2 and others depicted in this schematic diagram. The second mechanosensor in LECs, PIEZO1, activates the membrane-bound calcium channel ORAI1, leading to intracellular calcium entry. The major intracellular calcium sensor calmodulin forms a protein complex with KLF2, which subsequently drives lymphatics-related downstream gene upregulation or downregulation. Abbreviations: PIEZO1 Piezo type mechanosensitive ion channel component 1, ORAI1 calcium release-activated calcium channel protein 1, PECAM platelet and endothelial cell adhesion molecule, VE-cadherin vascular endothelial cadherin, VEGFR2 vascular endothelial growth factor receptor 2, VEGFR3 vascular endothelial growth factor receptor 2, YAP/TAZ yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), PI3K phosphoinositide 3-kinases, AKT serine/threonine-protein kinase, GATA2 GATA binding protein 2, KLF2 Krüppel-like factor 2, PROX-1 prospero homeobox protein 1, FOXC2 Forkhead box protein C2, NFATc1 calcineurin/NFAT, FOXP2 Forkhead box protein P2, Cx37 connexin37, Itga9 integrin alpha- 9/beta-1, Fat4 FAT tumor suppressor homolog 4, Vegfc vascular endothelial growth factor C, Vegfa vascular endothelial growth factor A, Fgfr3 fibroblast growth factor receptor 3, Dtx1 deltex E3 ubiquitin ligase 1, Dtx3 L deltex E3 ubiquitin ligase 3L. A letter P in the yellow circles indicates phosphorylation. Created with BioRender.com