Dayan, J. H. | bioRxiv Science

bioRxiv2025

GLP-1R Agonism Directly Improves the Pumping Capacity of Murine Collecting Lymphatic Vessels

BackgroundGlucagon-like peptide-1 receptor (GLP-1R) agonists have recently been suggested as effective therapies to treat or reduce the risk of developing secondary lymphedema in patients with obesity; however, it is unknown whether the observed improvement in lymphatic function is solely due to weight loss-associated systemic benefits or in synergy with a lymphatic-specific effect of these pharmacological therapies. MethodsWe assessed the expression and localization GLP-1Rs in and around the lymphatic vasculature by single-cell RNA sequencing and fluorescence confocal microscopy. Using pressure myography we evaluated the direct effects of GLP-1R agonist, semaglutide, on modulating the contractile activity of lymphatic vessels from healthy wild-type (WT) mice, as well as lymphatics from diet-induced obese (DIO) WT mice, and hypercholesterolemic ApoE KO mice. ResultsExpression of Glp1r (encoding GLP-1Rs) was detected solely in LECs and was highly enriched in LECs from collecting lymphatics but absent in LECs from capillary regions. Pharmacological activation of GLP-1Rs using semaglutide led to robust vasodilation and an increase in the pumping capacity of isolated collecting lymphatics from WT, DIO, and ApoE KO mice. Compared to WT controls, lymphatics from ApoE KO mice displayed significant contractile dysfunction, which was restored with semaglutide. The GLP-1R-mediated response was in part facilitated by nitric oxide (NO), NADPH oxidase-mediated reactive oxygen species (ROS), and potentially vasodilatory prostanoids. ConclusionsOur results revealed a direct, beneficial effect of GLP-1R agonism on lymphatic pumping capacity mediated by robust vasodilation, allowing lymphatics to accommodate larger fluid volumes, while maintaining strong and highly efficient contractions. Our observations implicated NO, ROS, and potentially vasodilatory prostanoids in the underlying mechanism; however, additional signaling components remain to be elucidated. These findings support recent clinical reports and further suggest that GLP-1R agonism could be an effective therapy for improving lymphatic contractile function in secondary lymphedema.

physiology↗

bioRxiv2023

Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema

Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.

immunology↗