Semaglutide alleviates atherosclerosis inflammation and endothelial dysfunction by activating the `Sema3A/NRP1` pathway in ApoE-/- mice.

Atherosclerosis (AS) is a chronic inflammatory disease of the arteries, a leading cause of cardiovascular events. Current treatments, while effective at managing lipid levels, often fall short in fully addressing the underlying inflammation and endothelial dysfunction, contributing to significant residual cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known for their metabolic benefits, but emerging evidence suggests broader anti-inflammatory and vascular protective effects. This study investigates how GLP-1 RAs, specifically through the Sema3A/NRP1 signaling pathway, might offer a novel therapeutic avenue for AS beyond glycemic control.

Researchers induced atherosclerosis in ApoE-/- mice by feeding them a 60 kcal% fat high-fat diet for 12 weeks. From weeks 13-24, mice (n=10/group) received either saline, 30/60 μg/kg semaglutide (L/H-GLP-1 RAs), or 1.3 mg/kg atorvastatin (positive control) via injections every 2 days. Body weight was monitored weekly. Rescue experiments used endothelial-specific NRP1 knockout (NRP1EC-KO) mice. In vitro, HUVECs were treated with 100 μg/mL ox-LDL for 24h to model endothelial dysfunction, then with 1/2 μM semaglutide or 10 μM atorvastatin. CCK-8 assays determined cell viability, and NRP1 inhibition with 0.5 μM NRP1 inhibitor EG01377 was used in rescue experiments.