Human lymphatic endothelial cells where EphrinB2 signaling has been blocked, show disrupted cell-cell junctions (in purple) and abundant stress fibers (in green). Image credit: Maike Frye (CC BY 4.0)
Lymph vessels are thin walled tubes that, similar to blood vessels, carry white blood cells, fluids and waste. Unlike veins and arteries, however, lymph vessels do not carry red blood cells and their main function is to remove excess fluid from tissues. The cells that line vessels in the body are called endothelial cells, and they are tightly linked together by proteins to control what goes into and comes out of the vessels. The chemical, physical and mechanical signals that control the junctions between endothelial cells are often the same in different vessel types, but their effects can vary.
The endothelial cells of both blood and lymph vessels have two interacting proteins on their membrane known as EphrinB2 and its receptor, EphB4. When these two proteins interact, the EphB4 receptor becomes activated, which leads to changes in the junctions that link endothelial cells together. Frye et al. examined the role of EphrinB2 and EphB4 in the lymphatic system of mice. When either EphrinB2 or EphB4 are genetically removed in newborn or adult mice, lymph vessels become disrupted, but no significant effect is observed on blood vessels. The reason for the different responses in blood and lymph vessels is unknown.
The results further showed that lymphatic endothelial cells need EphB4 and EphrinB2 to be constantly interacting to maintain the integrity of the lymph vessels. Further examination of human endothelial cells grown in the laboratory revealed that this constant signalling controls the internal protein scaffold that determines a cell’s shape and integrity. Changes in the internal scaffold affect the organization of the junctions that link neighboring lymphatic endothelial cells together.
The loss of signalling between EphrinB2 and EphB4 in lymph vessels reflects the increase in vessel leakage seen in response to bacterial infections and in some genetic conditions such as lymphoedema. Finding ways to control the signalling between these two proteins could help treat these conditions by developing drugs that improve endothelial cell integrity in lymph vessels.
