Lymphatic Vessels and Their Surroundings: How Local Physical Factors Affect Lymph Flow.

Simple Summary Lymphatic vessels are responsible for the drainage of liquids, solutes, and cells from interstitial spaces and serosal cavities. Their task is fundamental in order to avoid fluid accumulation leading to tissue swelling and edema. The lymphatic system does not possess a central pump, instead lymph is propelled against an overall hydraulic pressure gradient from interstitial spaces to central veins thanks to two pumping mechanisms, which rely on extrinsic forces or the intrinsic rhythmic contractility of lymphatic muscle cells embedded in vessel walls. This latter mechanism can very rapidly adapt to subtle changes in the microenvironment due to hydraulic pressure, lymph flow-induced wall shear stress, liquid osmolarity, and local tissue temperature. Thus, endothelial and lymphatic muscle cells possess mechanosensors that sense these stimuli and promote a change in contraction frequency and amplitude to modulate lymph flow accordingly. In this review, we will focus on the known physical parameters that can modulate lymph flow and on their putative cellular and molecular mechanisms of transduction. Lymphatic vessels drain and propel lymph by exploiting external forces that surrounding tissues exert upon vessel walls (extrinsic mechanism) and by using active, rhythmic contractions of lymphatic muscle cells embedded in the vessel wall of collecting lymphatics (intrinsic mechanism). The latter mechanism is the major source of the hydraulic pressure gradient where scant extrinsic forces are generated in the microenvironment surrounding lymphatic vessels. It is mainly involved in generating pressure gradients between the interstitial spaces and the vessel lumen and between adjacent lymphatic vessels segments. Intrinsic pumping can very rapidly adapt to ambient physical stimuli such as hydraulic pressure, lymph flow-derived shear stress, fluid osmolarity, and temperature. This adaptation induces a variable lymph flow, which can precisely follow the local tissue state in terms of fluid and solutes removal. Several cellular systems are known to be sensitive to osmolarity, temperature, stretch, and shear stress, and some of them have been found either in lymphatic endothelial cells or lymphatic muscle. In this review, we will focus on how known physical stimuli affect intrinsic contractility and thus lymph flow and describe the most likely cellular mechanisms that mediate this phenomenon.