Semaglutide enhances vascular relaxation to insulin in Western diet-fed female mice

Vascular insulin resistance is a hallmark of obesity and contributes to the development of cardiovascular disease. However, therapeutic strategies that restore insulin actions in the vasculature are largely lacking. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, were initially approved as glucose-lowering agents in type 2 diabetes and later for chronic body weight management. Subsequent studies have positioned GLP-1RAs in the realm of cardiovascular protective agents. Indeed, large outcome trials consistently demonstrate that GLP-1RAs lower blood pressure, reduce cardiovascular mortality and major adverse cardiovascular events, slow the progression of chronic kidney disease, and decrease hospitalizations for heart failure. Notably, these cardiovascular benefits exceed what would be expected from weight loss alone, suggesting direct tissue-protective effects of GLP-1RAs. Although evidence supports the notion that GLP-1RAs confer cardiovascular protection by mechanisms beyond weight loss, whether semaglutide enhances vascular insulin sensitivity remains less known. Herein, we tested the hypothesis that semaglutide treatment enhances vascular relaxation to insulin in a mouse model of diet-induced obesity. All data are reported as mean±SEM and significant differences were set at P< 0.05. Four-week-old female C57BL/6 mice were fed a Western diet for 24 weeks to induce obesity, and treated with daily subcutaneous semaglutide (9 nmol/kg) or vehicle during the last 8 weeks. As expected, semaglutide treatment reduced body weight (n=11-13, 32.45±1.92 vs 47.38±2.31 g), improved glucose tolerance (n=11-13, 0.86±0.03 vs 1.00±0.04 AUC fold difference), as assessed via glucose tolerance test, and reduced mean arterial pressure (n=10-13, 87.19±0.96 vs 92.83±1.71 mmHg), as assessed via tail cuff plethysmography. Insulin-induced relaxation, assessed via wire-myography in aortic rings, was enhanced in semaglutide-treated mice compared to controls (n=11-13, 21.25±2.72 vs 10.46±2.07%). Similarly, acetylcholine-induced relaxation was also augmented in the semaglutide group (n=11-13, 89.91±2.31 vs 80.04±1.62%). Endothelium-independent relaxation, assessed using sodium nitroprusside, was unaltered by semaglutide. These findings indicate that semaglutide improves indices of endothelial function, including vascular insulin sensitivity, in obese female mice. Follow-up experiments are underway to examine the underlying mechanisms by which semaglutide exerts insulin-sensitizing effects in the vascular endothelium. Funding: American Heart Association (24EIA1248820 to J.P.). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.