The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature

The lymphatic system is composed of a vascular network of thin-walled capillaries that drain protein-rich lymph from the extracellular spaces within most organs. A continuous single-cell layer of overlapping endothelial cells lines the lymphatic capillaries, which lack a continuous basement membrane and are, therefore, highly permeable. Lymph returns to venous circulation via the larger lymphatic collecting vessels, which contain a muscular and adventitial layer, and the thoracic duct. The lymphatic system also includes lymphoid organs such as the lymph nodes, tonsils, Peyer’s patches, spleen, and thymus, all of which play an important role in the immune response. The lymphatic system develops in parallel with the blood vascular system through a process known as lymphangiogenesis, and lymphatic vessels are not normally present in avascular structures such as epidermis, hair, nails, cartilage, and cornea, nor in some vascularized organs such as brain and retina. Although studies of normal development and pathologic growth of the blood vascular system have thoroughly elucidated the molecular mechanisms that control these angiogenic processes (Gale and Yancopoulos 1999), studies of the lymphatic system have been hindered by the lack of specific lymphatic markers and growth factors. Consequently, our understanding of the development and function of the lymphatic system and its role in disease is still emerging. Recently, the discovery of molecules that specifically control lymphatic development and lymphatic vessel growth (lymphangiogenesis) and the identification of new lymphatic endothelium-specific markers (Breiteneder-Geleff et al. 1999; Wigle and Oliver 1999; Jackson et al. 2001; Sleeman et al. 2001; Veikkola et al. 2001) have facilitated key scientific advances and provided new insights into the molecular mechanisms that control lymphatic development and function. These findings include the identification of specific genetic defects in certain hereditary diseases that are associated with lymphatic hypoplasia and dysfunction (i.e., lymphedemas; Milroy 1892; Meige 1898), and evidence that malignant tumors can directly activate lymphangiogenesis and lymphatic metastasis (Karpanen et al. 2001; Mandriota et al. 2001; Skobe et al. 2001a; Stacker et al. 2001).