Abstract
Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function.
Highlights
The endothelium of blood and lymphatic vessels forms a barrier that controls the movement of fluid, molecules, ions and cells between the blood/lymph and the tissue
The cell-cell junctions of lymphatic capillaries not targeted by the Pdgfb-CreERT2 transgene appeared disorganized in the Efnb2 mutant mice (Figure 1—figure supplement 1B), suggesting secondary effects caused by disruption of collecting vessels
We found that continuous basal EphrinB2/EphB4 signalling maintains cell junction stability selectively in lymphatic endothelial cell (LEC) by controlling Rac1/Rho-mediated regulation of the actin cytoskeleton and Claudin 5 (CLDN5) localisation
Summary
The endothelium of blood and lymphatic vessels forms a barrier that controls the movement of fluid, molecules, ions and cells between the blood/lymph and the tissue. The barrier function of endothelial cells (ECs) varies among different organs and vessel types. The blood brain barrier (BBB), for example, is formed of a continuous layer of ECs connected by specialized tight junctions and adherens junctions (Zhao et al, 2015). Blood vessels of the kidney and small intestine are lined by fenestrated ECs to facilitate rapid exchange, uptake and secretion of fluids, solutes and molecules (Aird, 2012). The architecture of lymphatic endothelial cell (LEC) junctions differs between the different vessel types (Baluk et al, 2007). Permeable button-like junctions of lymphatic capillaries allow uptake of fluid from the interstitium.
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