Abstract
PURPOSE: TGF-B1-a growth factor that regulates inflammation and fibrosis—is a key regulator of secondary lymphedema development. Angiotensin-converting enzyme (ACE) activity regulates TGF-B1 signaling in other organ systems; however, it is not known if ACE signaling plays an important role in lymphedema. The purpose of this study was therefore to analyze the expression of ACE in clinical samples, and determine if ACE inhibition is effective for treating the disease in a mouse model. METHODS: Matched upper extremity biopsies were collected from patients with unilateral breast cancer-related lymphedema (BCRL) and analyzed using immunofluorescence and qPCR. In addition, we used mouse models to analyze fibrosis, inflammation, lymphatic pumping, and lymphangiogenesis in animals treated with a topical formulation of Captopril, an ACE inhibitor. RESULTS: ACE expression was significantly increased in lymphedematous tissues of patients and in mouse models of lymphedema. Topical Captopril markedly decreased lymphedematous changes in the mouse tail by decreasing TGF-B1 expression and decreasing swelling, fibroadipose deposition, and inflammation. Captopril-treated animals also had significantly increased lymphatic collecting vessel pumping and collateral lymphatic formation. CONCLUSION: Topical Captopril significantly attenuates the pathological changes of lymphedema in a preclinical model. The use of topical formulations may help avoid systemic effects and holds promise in the clinical setting.
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