Lymphangiogenesis in Regenerating Tissue

Abstract

See related article, pages 1193–1199 The field of lymphangiogenesis has made rapid and exciting developments over the last few years more so than any other field in vascular biology.1 Progress in this field has been long awaited because a number of clinical disorders are associated with impaired lymphatic function. The lymphatic vasculature takes up fluid from the interstitial space, thereby maintaining interstitial fluid balance and providing lymphatic clearance of macromolecules. Abnormal development of lymphatic vessels can give rise to lymphatic malformations, large cystic structures in which lymphatic fluid accumulates. Mutations affecting the vascular endothelial growth factor receptor (VEGFR)-3, or the transcription factor forkhead box C2 (FOXC2), have been implicated in primary congenital lymphedema.2 Insufficient function of lymphatic vessels and lymphedema can also result from chronic inflammation, infection, or trauma. In addition to its function in fluid drainage, the lymphatic system is also an important route for circulating immune cells that function in immune surveillance, but also for the dissemination of metastatic tumor cells in the body.1 Consequently, there are a number of clinical applications for therapeutics that either inhibit or induce lymphangiogenesis. Until recently, the molecular mechanisms of lymphangiogenesis were largely unknown, mainly because molecular markers for lymphatic endothelium were lacking. However, several molecules that are expressed preferentially in lymphatic endothelium have recently been identified, including the VEGFR-3,1 the homeobox gene Prox-1,3 the hyaluronan receptor LYVE-1,4 and the mucin-type transmembrane glycoprotein podoplanin.5 Specific antibodies allowed the isolation and characterization of lymphatic endothelial cells.6 Forced expression of Prox1 in blood vessel endothelial cells caused upregulation of lymphatic markers such as Podoplanin or VEGFR-3, indicating that Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate.6,7 Florence Sabin proposed in 1902 that the lymphatic …