Semaglutide directly enhances lymphatic vessel pumping capacity by activating GLP-1 receptors in endothelial cells

Lymphedema, a chronic and debilitating condition characterized by fluid accumulation and tissue swelling, currently lacks effective pharmacological treatments. Existing therapies primarily focus on symptom management, highlighting a critical need for novel therapeutic strategies. Recent clinical observations have hinted that glucagon-like peptide-1 receptor (GLP-1R) agonists, widely used for type 2 diabetes and obesity, might reduce the risk or severity of secondary lymphedema. This study investigates the direct presence of GLP-1Rs in lymphatic vasculature and the functional impact of GLP-1R agonism on lymphatic vessel contractility, addressing a key gap in understanding this potential therapeutic mechanism.

Researchers first characterized Glp1r expression in and around lymphatic vasculature using single-cell RNA sequencing and fluorescence confocal microscopy. Subsequently, they evaluated the direct effects of the GLP-1R agonist, semaglutide, on modulating lymphatic contractility. This was performed using pressure myography on isolated collecting lymphatic vessels from wild-type (WT), diet-induced obese, and hypercholesterolemic ApoE knockout (KO) mice. The study aimed to determine if GLP-1R activation directly influences lymphatic pumping capacity and vasodilation.

Expression of Glp1r (encoding GLP-1Rs) was detected exclusively in lymphatic endothelial cells, confirming the direct presence of these receptors within the lymphatic system. Pharmacological activation of these GLP-1Rs with semaglutide led to robust vasodilation and a significant increase in the pumping capacity of isolated collecting lymphatics. This beneficial effect was consistently observed across all tested mouse models: WT, diet-induced obese, and hypercholesterolemic ApoE KO mice. The study also began to unravel the underlying mechanisms, suggesting that the GLP-1R-mediated response was partially facilitated by nitric oxide (NO) and its potential interaction with NaV channels. However, the full spectrum of involved signaling pathways remains to be completely elucidated. The ability of lymphatics to accommodate and displace larger fluid volumes while maintaining strong and highly efficient contractions was a key outcome.

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.