OBJECTIVES: Recent clinical studies have suggested that glucagon-like peptide-1 receptor (GLP-1R) agonists may be effective therapies to treat or reduce the risk of developing secondary lymphedema. In this study, we aimed to (1) determine if GLP-1Rs are present in the lymphatic vasculature and characterize their expression, and (2) assess the effects of GLP-1R agonism on the contractile function of collecting lymphatic vessels. METHODS: We assessed the expression of GLP-1Rs in and around the lymphatic vasculature by single-cell RNA sequencing and fluorescence confocal microscopy, and evaluated the direct effects of GLP-1R agonist, semaglutide, on modulating lymphatic contractility using pressure myography. RESULTS: Expression of Glp1r (encoding GLP-1Rs) was detected exclusively in lymphatic endothelial cells. Pharmacological activation of GLP-1Rs led to robust vasodilation and an increase in the pumping capacity of isolated collecting lymphatics from WT, diet-induced obese, and hypercholesterolemic ApoE KO mice. The GLP-1R-mediated response was in part facilitated by nitric oxide and its potential interaction with NaV channels; however, additional signaling remains to be elucidated. CONCLUSIONS: Our results revealed a direct, beneficial effect of GLP-1R agonism on lymphatic pumping capacity mediated by robust vasodilation, allowing lymphatics to accommodate and displace larger fluid volumes while maintaining strong and highly efficient contractions.
Schulz et al. (Tue,) studied this question.
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