<scp>GLP</scp> ‐1 Receptors Are Enriched in the Lymphatic Endothelium and Their Pharmacological Activation With Semaglutide Improves the Pumping Capacity of Lymphatic Vessels

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.