Empagliflozin Promotes Revascularization in Diabetic Mice Hindlimb Ischemia by Improving Vascular Endothelial Cell Function.

Empagliflozin (EMPA), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, offers vascular protection beyond its glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). As endothelial dysfunction is a key initiator of vascular disease, understanding the precise regulatory mechanisms of EMPA in diabetic vascular complications is of great interest. In this study, we evaluated the therapeutic potential of EMPA in promoting blood flow recovery and revascularization under diabetic conditions using a hindlimb ischemia (HLI) model in db/db mice. We also investigated the effects of EMPA on the angiogenic function of endothelial cells exposed to high glucose and palmitate (HG/PA) conditions, mimicking the metabolic milieu of T2DM. The results demonstrated that EMPA significantly improved blood perfusion recovery in ischemic limbs, concomitant with enhanced angiogenesis and arteriogenesis in the ischemic gastrocnemius muscle. At the cellular level, EMPA effectively preserved endothelial function by mitigating HG/PA-induced impairments in cell migration and tube formation. Notably, EMPA treatment substantially ameliorated diabetes-induced oxidative stress in both muscle tissues and endothelial cells. Mechanistic studies revealed that EMPA upregulated antioxidant gene expression through SETD2-mediated pathways, thereby restoring endothelial angiogenic function under diabetic conditions. Taken together, these findings highlight that EMPA's therapeutic potential in diabetic HLI by attenuating oxidative stress and enhancing endothelial function.