Objective: Secondary lymphedema commonly arises as a complication of cancer surgery and radiation treatment; however, the underlying mechanisms are poorly understood. We recently found that thromboxane A₂ has pro-lymphangiogenic effects in inflamed tissues. The present study examined whether thromboxane A₂ receptor (TP) signaling plays a role in increased lymphangiogenesis during secondary lymphedema.
Methods and Results: A model of lymphedema was generated by surgical removal of pre-existing lymphatic vessels from the subcutaneous tissue on the tails of TP knockout (TPKO) mice and their wild-type (WT) counterparts. Compared with that in WT mice, lymphedema in the tails in TPKO mice was sustained, with suppressed lymphangiogenesis and expression of lymphangiogenic factors. The number of macrophages in TPKO was higher than that in WT mice. Expression of genes related to inflammatory macrophages in TPKO mice was higher than in WT mice, whereas expression of reparative macrophages was lower. Similar results were obtained in macrophage-specific TPKO mice and control mice.
Conclusions: In a secondary lymphedema model, endogenous thromboxane acts on TP in macrophages and promotes lymphangiogenesis, thereby contributing to the reduction of lymphedema.