Indole‐3‐Propionic Acid Improves Vascular Function in High‐Fat Diet‐Induced Obese Mice via eNOS

ABSTRACT Background The gut microbiota‐derived metabolite indole‐3‐propionic acid (IPA) has been implicated in vascular homeostasis; however, its role in mesenteric vascular function and blood pressure regulation under obese conditions remains unclear. This study aimed to investigate the effects of IPA on mesenteric vascular endothelial function and blood pressure in high‐fat diet‐induced obese (DIO) mice. Methods C57BL/6 mice were fed a high‐fat diet for 3 months to induce the DIO model. DIO mice were gavaged daily with IPA (20 mg/kg) for 6 weeks. At the end of the treatment, inflammatory markers and nitric oxide (NO) levels in primary mesenteric artery endothelial cells were assessed by qPCR and fluorescence staining, respectively. Vascular relaxation function of the mesenteric arteries was measured via wire myograph. Additionally, the immediate effect of IPA on blood pressure was monitored via the tail‐cuff method following IPA injection. Results The results demonstrated that IPA treatment significantly reduced the levels of inflammatory cytokines in the endothelial cells of DIO mice. IPA administration markedly increased NO levels in endothelial cells and enhanced the endothelium‐dependent vasodilation of mesenteric arteries. Mechanistically, IPA enhanced the phosphorylation of endothelial nitric oxide synthase (eNOS) via the PI3K/Akt pathway, promoting the production and release of NO, thereby regulating blood pressure. This was further validated in eNOS −/− mice. Conclusion This study reveals the vascular protective effects of IPA in obesity, providing new insights for the treatment of obesity‐related cardiovascular diseases.