The role of exercise in promoting lymphangiogenesis and extracellular matrix synthesis in lymphedema-induced tissue injury

Background: Secondary lymphedema is a progressive condition caused by lipid- and protein-rich interstitial fluid accumulation resulting from compromised lymphatic function. It commonly occurs in cancer patients following surgical lymph node ablation and radiation treatment. This study aims to elucidate the effects of exercise on the myokine interleukin (IL)-6 and the molecular changes involved in lymphangiogenesis and extracellular matrix (ECM) synthesis using a lymphedema mouse model.

Methods and results: We induced lymphedema in male ICR mice by excising the inguinal, popliteal, and iliac lymph nodes and occluding the femoral lymphatic vessel in the right hind leg. We then conducted a time course analysis of swelling and targeted gene expression analysis of the affected leg tissue. We began the mice on involuntary wheel running exercise 2 days post-surgery. Over the subsequent 2 weeks, the swelling initially increased and then gradually declined. In contrast, the genes associated with lymphangiogenesis and ECM synthesis showed progressive upregulation, even after the swelling had subsided. Exercise reduced limb swelling and increased the genetic expression of IL-6 and key lymphangiogenesis markers, including Prox1, VEGF-C, VEGFR-3, and LYVE-1, in the affected limb. Exercise also increased the expression of FABP4 and αSMA, which are markers of active adipocytes and fibroblasts.

Conclusions: Our results suggest that exercise reduces lymphedema by promoting lymphangiogenesis and ECM synthesis, facilitating recovery. The insights obtained into the molecular changes underpinning exercise-induced improvements in lymphedema may contribute to the development of targeted therapeutic strategies.