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