Lymphatic Endothelial Junctions

Junctions between lymphatic endothelial cells have a paucity of tight junction desmosomes (macula adherents) and interendothelial membrane adhesion molecules, such as VE-cadherins, desmoplakin, or plakoglobin. The cell extensions at the junctions form overlapping cellular flaps, which have the ability to separate from each other because of the lack of interendothelial adhesion molecules. These cell extensions are not attached to the underlying tissue matrix; they form the part of an endothelial cell that can form a small flap (see the following section).

The Primary Lymphatic Valves

Investigation of lymphatic endothelial sections fixed during lymph pumping shows open interendothelial junctions not found in resting initial lymphatics. These results suggest that initial lymphatics have a (primary) valve system at the level of the endothelial junctions. Cross sections through the initial lymphatics show open lymphatic endothelial flaps in muscle that during tissue fixation has been periodically compressed to preserve lymph flow into the lymphatic channel. No open junctions can be observed on cross sections of initial lymphatics fixed in a resting state without oscillatory muscle compression. Colloidal tracer particles can readily enter into the lumen of the initial lymphatics. But inside the lumen of the initial lymphatics, no significant escape of tracer particles out of the lymph lumen occurs. Escape of tracer particles from the lymphatic lumen is small, even after lowering the fluid pressure in the interstitium adjacent to the initial lymphatics.

The primary lymphatic valves can open and close rapidly, possibly by a mechanical flap action of overlapping cell extensions at the endothelial junctions [7]. The initial lymphatic endothelium serves as a unidirectional transport barrier. This particular endothelium is leaky when fluid enters from the interstitial space, but it is tight for fluid transport in the reverse direction.

The Secondary Intralymphatic Valves

Lymphatics have a system of intraluminal (secondary) valves that prevent reflow along the length of the lymphatic channels. The valves have bileaflet morphology with the individual valves made up of a thin collagen sheet sandwiched between two layers of endothelial cells. The valve leaflets are relatively long (typically about twice the length of the lymph cross-sectional dimension), forming a funnel inside the lymphatic channels. This feature facilitates the opening and closing of the secondary valves by fluid pressure drops across the leaflets generated by viscous pressure gradients inside the funnel. Secondary valves also operate in lymphatics with highly irregular lumen cross sections.

The spacing of secondary valves along the initial lymphatics is organ dependent. For example, in the intestinal wall there are relatively few secondary valves, whereas in skeletal muscle they frequently arise at convergent bifurcations of two lymphatic channels into a single daughter vessel, preventing reflow into the two parent channels. Contractile lymphatics in general have secondary valves, arranged in a ladder configuration, designated as lymphan-gions. Each lymphangion consists of a contractile compartment with an inlet and an outlet valve.

The Interplay between Primary and Secondary Lymphatic Valves

In the presence of two valve systems, the unidirectional transport in lymphatics is easy to understand. Consider two periods during a pump cycle, an expansion period and a compression period of an initial lymphatic (Figure 3). During lymphatic expansion, an initial lymphatic channel becomes filled with interstitial fluid. During this period the primary lymphatic valves are open and the secondary valves inside the lumen are closed to prevent reflow of fluid along the lymphatic duct. During lymphatic compression, the primary valves close and prevent escape of fluid back into the interstitium while the secondary valves in the lymphatic lumen are open. Thus fluid is transported along the lumen of the initial lymphatics in a proximal direction toward the contractile lymphatics and nodes. During each compression and expansion of initial lymphatics, the cycle repeats.

Compartments that rely on volume expansion and compression as the primary mode of fluid movement require two valves for unidirectional transport. For example, a lymphan-gion along the contractile lymphatics has two valves, one at the entry and one at the exit from the lymphangion. Puncturing one of the valves compromises the fluid transport in and out of the lymphangion. A chain of lymphangions, as seen along the contractile lymphatics, serves as entry and exit valves from one such compartment to the next.

Leakage of the Primary Valves and Tissue Edema

The interendothelial junctions can be readily separated if tension is applied to the lymphatic wall, for example by overinflation of the lymphatic lumen [8]. There are local regions along the interendothelial junctions where neighboring endothelial cells can be separated when tension is applied to them. When these junctions are stretched open, one can identify endothelial attachment to the underlying

Initial Lymphatic

Contractile Lymphatic

Primary Lymphatic Valves Compression Cyc|e Secondary Lymphatic Valves

Primary Lymphatic Valves Compression Cyc|e Secondary Lymphatic Valves v-

Expansion Cycle

Figure 3 Schematic of opening and closing of primary and secondary lymph valves in microlymphatic during expansion and compression cycle of the initial lymphatics. During expansion, the primary valves are open to permit fluid entry from the interstitium, while secondary valves are closed to prevent reflow inside the lymphatic lumen. During compression, the primary valves are closed to prevent reflow into the interstitium, while the secondary valves are open for discharge toward the central lymphatics.

Figure 3 Schematic of opening and closing of primary and secondary lymph valves in microlymphatic during expansion and compression cycle of the initial lymphatics. During expansion, the primary valves are open to permit fluid entry from the interstitium, while secondary valves are closed to prevent reflow inside the lymphatic lumen. During compression, the primary valves are closed to prevent reflow into the interstitium, while the secondary valves are open for discharge toward the central lymphatics.

basement membrane and to anchoring filaments, and can detect large openings between endothelial cells that permit free fluid entry in and out of the initial lymphatics. The primary lymphatic valves may cease functioning under edematous conditions.

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