Current views on the function of the lymphatic vasculature in health and disease

Abstract

The lymphatic vascular system is essential for lipid absorption, fluid homeostasis, and immune surveillance. Until recently, lymphatic vessel dysfunction had been associated with symptomatic pathologic conditions such as lymphedema. Work in the last few years had led to a better understanding of the functional roles of this vascular system in health and disease. Furthermore, recent work has also unraveled additional functional roles of the lymphatic vasculature in fat metabolism, obesity, inflammation, and the regulation of salt storage in hypertension. In this review, we summarize the functional roles of the lymphatic vasculature in health and disease.

Figure 1.

The lymphatic vascular network includes blind-ended capillaries and larger collecting lymphatic vessels. The lymphatic capillaries are composed of a single layer of overlapping ECs and lack a continuous basement membrane. Collecting lymphatic vessels are covered by smooth muscle cells, and possess a basement membrane and luminal valves that prevent lymph backflow. The unique structure of capillary lymphatic vessels allows for the uptake of interstitial fluid, macromolecules, cells, and lipids that filtrate continuously from the blood capillary network.

Figure 2.

Different types of alterations in the lymphatic vascular network can lead to a variety of pathological conditions or impact the inflammatory or immune responses. Hypoplastic, hyperplastic, mispatterned, or damaged (e.g., mechanical) lymphatics can result in different types of primary or secondary lymphedema. Meanwhile, leaky lymphatics can promote obesity.

Figure 3.

Lymph nodes are the most common site for the metastatic spread of tumor cells, and tumor propagation to lymph nodes is one of the main prognostic indicators. As tumor cells reach the sentinel lymph node, they will spread into distant lymph nodes and other organs. (A) One of the mechanisms of tumor-associated lymphangiogenesis involves the release of VEGF-C or VEGF-D by tumor cells or TAMs, stimulating the growth of additional peritumoral (and, in some cases, also intratumoral) lymphatic vessels and the dilation of pre-existing lymphatic vessels. This in turn facilitates the entry of tumor cells into the lumen of the lymphatic vessels, possibly via interactions between tumor cells and LECs. Therefore, inhibition of tumor lymphangiogenesis by blocking the VEGF-C/VEGFR-3 signaling pathway could be an efficient approach aimed to suppress lymph node metastasis. (B) Lymph node lymphangiogenesis has also been shown recently to promote tumor metastasis. In this case, growth factors such as VEGF-C or VEGF-A produced by the primary tumor can act at a distance by inducing lymphangiogenesis in the sentinel lymph node prior to the arrival of the first metastatic cells and, eventually, promoting additional cancer metastasis to distant lymph nodes and organs.