Blood and lymphatic vessel networks form two arms of the vertebrate cardiovascular system that play complementary roles in body homeostasis maintenance and multiple diseases. Lymphatic vessels are lined with lymphatic endothelial cells (LECs), which represent a distinct endothelial cell lineage characterized by a specific transcriptional and metabolic program. The general functions of lymphatic vessels in fluid transport and immunosurveillance are well recognized, as is their specialization into capillaries, serving as an entrance point of interstitial components and immune cells and collecting vessels that deliver lymph to lymph nodes (LNs) and blood circulation. It is becoming increasingly clear that adult lymphatic vessels, exposed to different organ-specific environments, acquire distinct characteristics and in turn execute multiple tissue-specific functions.

This Review provides an overview of the recent advances in our understanding of new functions of adult mammalian lymphatic vessels, such as immunomodulation, contribution to neurodegenerative and neuroinflammatory diseases, and response to anticancer therapies. LN LECs have been shown to archive antigens and directly regulate immune cell properties, including immune cell survival and positioning within the LN. Rediscovery of meningeal lymphatic vessels has uprooted the dogma of brain immune privilege, and these vessels now emerge as key regulators of neuroinflammation and neurodegeneration. Intestinal lacteals display distinct cellular characteristics that make them especially suitable for dietary fat uptake and designate them as promising targets for the treatment of obesity. Tumor lymphatics have long been recognized as conduits for metastatic cell dissemination; however, recent data show that lymphatic vessels have multiple additional functions, such as forming metastatic cancer cell niches but also controlling productive response to antitumor immune therapies. Last, discovery of vascular beds with hybrid blood and lymphatic characteristics, such as the Schlemm’s canal in the eye and the kidney ascending vasa recta, underscores the degree and potential of endothelial cell plasticity.

Molecular characteristics of organ-specific vascular beds and understanding their organotypic functions are among the current fundamental questions of vascular biology. Emerging evidence points to the major contribution of lymphatic vessels, a vascular system generally associated only with tissue-drainage functions. High-resolution analyses of endothelial heterogeneity and organotypic lymphatic vessel architecture, in addition to deciphering the molecular codes that LECs use for communication with other cell types, are necessary to fully understand the role of lymphatics in organ physiology and pathology. Integration of such knowledge with research from other fields, such as immunology and bioengineering, will uncover new possibilities for promoting tissue regeneration and developing new therapies for cancer, obesity, neuroinflammation, and neurodegeneration.

(Left) Small intestine. Shown are LYVE-1⁺ (green) lacteal, CD31⁺(red) capillary plexus, and α-smooth actin⁺ (blue) longitudinal smooth muscle cells. (Middle) Meninges. Shown are LYVE-1⁺ (green) and VEGFR3⁺ (blue) lymphatic vessels and CD31⁺ (red) blood vessels. (Right) LN. Shown are LYVE-1⁺ (green) lymphatic vessels and CD31⁺(red) blood vessels, including high endothelial venules.