Endothelial dysfunction initiates and exacerbates hypertension, atherosclerosis and other cardiovascular complications in diabetic mellitus. FGF21 is a hormone that mediates a number of beneficial effects relevant to metabolic disorders and their associated complications. Nevertheless, it remains unclear as to whether FGF21 ameliorates endothelial dysfunction. Therefore, we investigated the effect of FGF21 on endothelial function in both type 1 and type 2 diabetes. We found that FGF21 reduced hyperglycemia and ameliorated insulin resistance in type 2 diabetic mice, an effect that was totally lost in type 1 diabetic mice. However, FGF21 activated AMPKα, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of aorta in both types, suggesting a mechanism that is independent of its glucose-lowering and insulin-sensitizing effects. In vitro, we identified a direct action of FGF21 on endothelial cells of the aorta, in which it bounds to FGF receptors to alleviate impaired endothelial function challenged with high glucose. Furthermore, the CaMKK2-AMPKα signaling pathway was activated to suppress oxidative stress. Apart from its anti-oxidative capacity, FGF21 activated eNOS to dilate the aorta via CaMKK2/AMPKα activation. Our data suggest expanded potential uses of FGF21 for the treatment of vascular diseases in diabetes.

内皮功能障碍会引发并加剧糖尿病患者的高血压，动脉粥样硬化和其他心血管并发症。FGF21是一种激素，可介导许多与代谢紊乱及其相关并发症有关的有益作用。然而，关于FGF21是否改善内皮功能障碍尚不清楚。因此，我们研究了FGF21对1型和2型糖尿病患者内皮功能的影响。我们发现，FGF21降低了2型糖尿病小鼠的高血糖症并改善了其胰岛素抵抗，这一作用在1型糖尿病小鼠中完全消失了。但是，两种类型的FGF21均能激活AMPKα，抑制氧化应激并增强内皮依赖性主动脉的血管舒张，提示其机制独立于其降糖和胰岛素增敏作用。在体外，我们确定了FGF21对主动脉内皮细胞的直接作用，其中它与FGF受体结合，以缓解高糖激发的受损内皮功能。此外，CaMKK2-AMPKα信号通路被激活以抑制氧化应激。FGF21除了具有抗氧化能力外，还通过CaMKK2 /AMPKα激活来激活eNOS来扩张主动脉。我们的数据表明，FGF21在糖尿病血管疾病的治疗中具有广泛的潜在用途。CaMKK2-AMPKα信号通路被激活以抑制氧化应激。FGF21除了具有抗氧化能力外，还通过CaMKK2 /AMPKα激活来激活eNOS来扩张主动脉。我们的数据表明，FGF21在糖尿病血管疾病的治疗中具有广泛的潜在用途。CaMKK2-AMPKα信号通路被激活以抑制氧化应激。FGF21除了具有抗氧化能力外，还通过CaMKK2 /AMPKα激活来激活eNOS来扩张主动脉。我们的数据表明，FGF21在糖尿病血管疾病的治疗中具有广泛的潜在用途。