Lymphatic Endothelial Cell Junctions: Molecular Regulation in Physiology and Diseases

Abstract

Lymphatic endothelial cells (LECs) lining lymphatic vessels develop specialized cell-cell junctions that are crucial for the maintenance of vessel integrity and proper lymphatic vascular functions. Successful lymphatic drainage requires a division of labor between lymphatic capillaries that take up lymph via open "button-like" junctions, and collectors that transport lymph to veins, which have tight "zipper-like" junctions that prevent lymph leakage. In recent years, progress has been made in the understanding of these specialized junctions, as a result of the application of state-of-the-art imaging tools and novel transgenic animal models. In this review, we discuss lymphatic development and mechanisms governing junction remodeling between button and zipper-like states in LECs. Understanding lymphatic junction remodeling is important in order to unravel lymphatic drainage regulation in obesity and inflammatory diseases and may pave the way towards future novel therapeutic interventions.

Keywords: VE-cadherin; VEGFR2 signaling; button-like junction; endothelial junction; lymphatic vessel; zipper-like junction.

FIGURE 1

Schematic of morphology, localization and protein components of LEC junctions. LECs lining initial and collecting lymphatics develop different cell-cell junctions to execute uptake and transport of lymph, respectively. The specialized discontinuous buttons in initial lymphatics serve as anchoring sites at the sides of interdigitated flaps of adjacent oak leaf-shaped LECs, and the loosely apposed border regions between buttons are entry sites for fluids, chylomicrons and immune cells. The endothelium of collecting vessels has continuous zippers that prevent vascular leak and allow transport of lymph, a process that is aided by smooth muscle cell coating and intraluminal valves. Adherens junction- and tight junction-associated proteins are enriched in both buttons and zippers. In mature initial lymphatics, most PECAM-1 and LYVE-1 are distributed at the tips of flaps between buttons. LEC, lymphatic endothelial cell.

FIGURE 2

Regulation of endothelial cell-cell junctions by VEGF-A/VEGFR2 signaling in intestinal villi. VEGF-A bioavailability for VEGFR2 is limited due to VEGF-A binding to FLT1 and NRP1 which are only highly expressed in BECs. This results in continuous junctions in BECs and discontinuous buttons in LECs that allow for lacteal chylomicron uptake. Increased levels of VEGF-A or deletion of Nrp1 and Flt1 in BECs leads to upregulated signaling through VEGFR2, which disrupts BEC junctions and, opposingly, leads to lacteal junction transformation from buttons to zippers. As a result, chylomicron uptake by lacteals is inhibited, rendering mice resistant to diet-induced obesity. BEC, blood endothelial cell; LEC, lymphatic endothelial cell; NRP1, neuropilin1; FLT1, Fms-related tyrosine kinase 1 (or VEGFR1).