Progress and prospect of lymphangiogenesis research

During the last twenty years, we have witnessed a rapid progress in the field of lymphatic vascular biology. The increase of lymphatic research has greatly deepened our understanding of the lymphatic system in health as well as in diseases. This review starts with the description of the current understanding of the mechanism underlying lymphatic formation and remodeling in development. In mammals, lymphatic vessel development initiates with the specification of lymphatic endothelial cells from a population of venous endothelial cells in the lateral parts of the anterior cardinal veins. This is followed by the formation of lymph sacs, which undergoes expansion into the primitive lymphatic plexus by the process of lymphangiogenesis. The primary lymphatic network is further remodeled into a mature lymphatic system composed of lymphatic capillaries and collecting lymphatics containing intraluminal valves as well as smooth muscle cell coverage. Several key factors and pathways have been identified to participate in the process, including lymphangiogenic growth factors and receptors, extracellular matrix proteins and cell junction molecules, intracellular signal mediators and transcription factors. It is interesting to find out how these factors coordinate to control collecting vessel formation and maturation, and whether they work in the same pathway or in different pathways controlling specific cellular programs. Secondly, the authors summarize the physiological functions of lymphatic system, including the essential role of lymphatic system in the maintenance of tissue fluid homeostasis. Defective lymphatic development or damage of the lymphatic system resulting from surgery or infection leads to lymphedema. In immune system, lymphatic vessels are crucial for the leukocyte trafficking from peripheral tissues to their draining lymph nodes and for the drainage of soluble antigens. Furthermore, the absorption of dietary nutrients is critically dependent on the lymphatic vessels in intestines, also known as lacteals in intestinal villi. Finally, the authors have discussed the involvement of lymphatic system in several diseases including tumor metastasis, inflammation and cardiovascular diseases. It has also been well established that tumor associated lymphangiogenesis promotes lymphogenous tumor metastasis. Although the molecular players responsible for lymphatic vessel growth is similar in development and tumor, there are distinct characteristics of tumor-associated lymphangiogenesis, including the lack of lymphangiogenic growth factor gradient in tumor. Therefore, tumor-associated lymphatics are patchy, disorganized without a hierarchical vascular pattern, and also not homogenously distributed within tumors. In addition, inflammation is often associated with profound lymphatic vessel growth and remodeling, and there are also evidence showing that the abnormal lymphatic growth is implicated in cardiovascular diseases. In spite of the recent progress in the research field of lymph-vascular biology, there is still lack of effective drugs for the prevention and treatment of lymphedema and lymphatic related diseases. Thus, continued support and further increase in research investment in this field are very much wanted to better understand the cellular events and molecular players involved in lymphatic vessel growth and function at both physiological and pathological conditions.