The lymphatic vascular system: much more than just a sewer

Abstract Almost 400 years after the (re)discovery of the lymphatic vascular system (LVS) by Gaspare Aselli (Asellius G. De lactibus, sive lacteis venis, quarto vasorum mesaraicorum genere, novo invento Gasparis Asellii Cremo. Dissertatio. (MDCXXIIX), Milan; 1628.), structure, function, development and evolution of this so-called ‘second’ vascular system are still enigmatic. Interest in the LVS was low because it was (and is) hardly visible, and its diseases are not as life-threatening as those of the blood vascular system. It is not uncommon for patients with lymphedema to be told that yes, they can live with it. Usually, the functions of the LVS are discussed in terms of fluid homeostasis, uptake of chylomicrons from the gut, and immune cell circulation. However, the broad molecular equipment of lymphatic endothelial cells suggests that they possess many more functions, which are also reflected in the pathophysiology of the system. With some specific exceptions, lymphatics develop in all organs. Although basic structure and function are the same regardless their position in the body wall or the internal organs, there are important site-specific characteristics. We discuss common structure and function of lymphatics; and point to important functions for hyaluronan turn-over, salt balance, coagulation, extracellular matrix production, adipose tissue development and potential appetite regulation, and the influence of hypoxia on the regulation of these functions. Differences with respect to the embryonic origin and molecular equipment between somatic and splanchnic lymphatics are discussed with a side-view on the phylogeny of the LVS. The functions of the lymphatic vasculature are much broader than generally thought, and lymphatic research will have many interesting and surprising aspects to offer in the future.