Limited Proteolysis as a Regulator of Lymphatic Vessel Function and Architecture

Recent advances have highlighted the multifaceted roles of the lymphatic vasculature in immune cell trafficking, immunomodulation, nutrient transport, and fluid homeostasis. Beyond these physiological functions, lymphatic vessels are critically involved in pathologies such as cancer metastasis and lymphedema, rendering their structural and functional regulation of major interest. Emerging evidence suggests that limited proteolysis is a key regulatory mechanism for lymphatic vascular function. In dyslipidemic conditions, dysregulated calpain activity impairs lymphatic trafficking and destabilizes regulatory T cells, partly via the limited proteolysis of mitogen-activated kinase kinase kinase 1 and inhibitor of κBα. In addition, a disintegrin and metalloprotease with thrombospondin motifs-3-mediated proteolytic activation of vascular endothelial growth factor-C has been implicated in both developmental and tumor-associated lymphangiogenesis. Proteolytic shedding of lymphatic vessel endothelial hyaluronan receptor-1 by a disintegrin and metalloprotease 17 promotes lymphangiogenesis, whereas cleavage by membrane-type 1 matrix metalloproteinase inhibits it. This review is structured around two core aspects-lymphatic inflammation and lymphangiogenesis-and highlights recent findings on how limited proteolysis regulates each of these processes. It also discusses the therapeutic potential of targeting these proteolytic machineries and currently unexplored research questions, such as how intercellular junctions of lymphatic endothelial cells are controlled.