Functionally specialized junctions between endothelial cells of lymphatic vessels

Abstract

Recirculation of fluid and cells through lymphatic vessels plays a key role in normal tissue homeostasis, inflammatory diseases, and cancer. Despite recent advances in understanding lymphatic function (Alitalo, K., T. Tammela, and T.V. Petrova. 2005. Nature. 438:946–953), the cellular features responsible for entry of fluid and cells into lymphatics are incompletely understood. We report the presence of novel junctions between endothelial cells of initial lymphatics at likely sites of fluid entry. Overlapping flaps at borders of oak leaf–shaped endothelial cells of initial lymphatics lacked junctions at the tip but were anchored on the sides by discontinuous button-like junctions (buttons) that differed from conventional, continuous, zipper-like junctions (zippers) in collecting lymphatics and blood vessels. However, both buttons and zippers were composed of vascular endothelial cadherin (VE-cadherin) and tight junction–associated proteins, including occludin, claudin-5, zonula occludens–1, junctional adhesion molecule–A, and endothelial cell–selective adhesion molecule. In C57BL/6 mice, VE-cadherin was required for maintenance of junctional integrity, but platelet/endothelial cell adhesion molecule–1 was not. Growing tips of lymphatic sprouts had zippers, not buttons, suggesting that buttons are specialized junctions rather than immature ones. Our findings suggest that fluid enters throughout initial lymphatics via openings between buttons, which open and close without disrupting junctional integrity, but most leukocytes enter the proximal half of initial lymphatics.

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

“…It is characterized by a network of vessels that carry a clear fluid called lymph. Sequentially, ultrafiltrates from peripheral tissues are absorbed by initial lymphatics (also called lymphatic capillaries), a highly permeable and specialized compartment constituted by discontinuous “button‐like” junctions between endothelial cells 2. These initial lymphatics are characterized by the absence of smooth muscle cells and the presence of lymphatic vessel endothelial hyaluronan receptor (LYVE‐1) at the surface of lymphatic endothelial cells (LECs) 3.…”

Distinct molecular composition of blood and lymphatic vascular endothelial cell junctions establishes specific functional barriers within the peripheral lymph node

“…Thus, presence of ESAM-1 in cell contacts of LYVE-1 + lymphatic endothelium seems to be restricted to the sinus-lining endothelial cells, further supporting a potential role in immune cell diapedesis across this cellular barrier. Recent findings demonstrating the presence of ESAM-1 in cell junctions of initial and collecting lymphatics in the mouse trachea may even further support this notion, as in the lung and its associated tissues immune cell diapedesis usually occurs at the capillary level [33].…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Interstitial fluid drains into lymphatic capillaries (also known as initial lymphatics and terminal lymphatics) that are blind-ended vessels with a discontinuous basement membrane that lack pericytes. The interendothelial adhesions are maintained by discontinuous, "button-like" junctions serving to both freely drain interstitial proteins and also facilitate immune cell transmigration [28][29][30][31]. These overlapping cell-cell junctions serve as primary valves to prevent backflow from the lymphatic vessel into the tissue [32] and secondary valves prevent backflow within the vessel [33].…”

“…These overlapping cell-cell junctions serve as primary valves to prevent backflow from the lymphatic vessel into the tissue [32] and secondary valves prevent backflow within the vessel [33]. These capillaries drain into precollecting and collecting vessels that have continuous, "zipper-like" interendothelial junctions [30] and are surrounded by smooth muscle. Collecting vessels are organized into contractile segments called lymphangions, separated by bileaflet valves, that create the driving force for unidirectional lymph propulsion [30,31,[34][35][36].…”

“…These capillaries drain into precollecting and collecting vessels that have continuous, "zipper-like" interendothelial junctions [30] and are surrounded by smooth muscle. Collecting vessels are organized into contractile segments called lymphangions, separated by bileaflet valves, that create the driving force for unidirectional lymph propulsion [30,31,[34][35][36]. Collecting lymphatic vessels that carry lymph to and from the lymph nodes are referred to as afferent and efferent lymphatic vessels, respectively.…”