Dokun Ayotunde O, Chen Lingdan, Lanjewar Swapnil S, Lye Robert John, Annex Brian H
Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22901, USA.
Cardiovasc Res. 2014 Mar 1;101(3):364-72. doi: 10.1093/cvr/cvt342. Epub 2014 Jan 2.
Diabetes mellitus (DM) is associated with poor clinical outcomes in humans with peripheral arterial disease (PAD) and in pre-clinical models of PAD, but the effects of glycaemic control are poorly understood. We investigated the effect of glycaemic control on experimental PAD in mice with Type 1 DM and explored the effects of hyperglycaemia on vascular endothelial growth factor receptor 2 (VEGFR2) expression in ischaemia.
Hind limb ischaemia was induced in non-diabetic, untreated Type 1 DM, and treated Type 1 DM mice. We assessed perfusion recovery, capillary density, VEGFR2 levels, and VEGFR2 ubiquitination in ischaemic hind limbs. We found that untreated Type 1 DM mice showed impaired perfusion recovery, lower hind limb capillary density 5 weeks post-ischaemia, and lower VEGFR2 protein in Day 3 post-ischaemic hind limbs when compared with non-DM controls. Treated Type 1 DM mice had perfusion recovery, capillary density, and VEGFR2 protein levels comparable with that of non-diabetic mice at the same time points. Treatment with anti-VEGFR2 antibody negated that the improved perfusion recovery displayed by treated Type 1 DM mice. In ischaemic Type 1 DM hind limbs and endothelial cells exposed to simulated ischaemia, high glucose impaired VEGFR2 expression and was associated with increased VEGFR2 ubiquitination. Inhibition of the ubiquitin-proteasome complex restored normal endothelial VEGFR2 expression in simulated ischaemia.
Hyperglycaemia in Type 1 DM impairs VEGFR2 protein expression in ischaemic hind limbs, likely due to increased ubiquitination and degradation by the proteasome complex. Glycaemic control allows normal levels of VEGFR2 in ischaemia and improved perfusion recovery.
糖尿病（DM）与外周动脉疾病（PAD）患者及PAD临床前模型的不良临床结局相关，但血糖控制的影响尚不清楚。我们研究了血糖控制对1型糖尿病小鼠实验性PAD的影响，并探讨了高血糖对缺血状态下血管内皮生长因子受体2（VEGFR2）表达的影响。
对非糖尿病、未经治疗的1型糖尿病和经治疗的1型糖尿病小鼠诱导后肢缺血。我们评估了缺血后肢的灌注恢复、毛细血管密度、VEGFR2水平和VEGFR2泛素化。我们发现，与非糖尿病对照组相比，未经治疗的1型糖尿病小鼠在缺血后5周显示灌注恢复受损、后肢毛细血管密度较低，且在缺血后第3天缺血后肢的VEGFR2蛋白水平较低。经治疗的1型糖尿病小鼠在相同时间点的灌注恢复、毛细血管密度和VEGFR2蛋白水平与非糖尿病小鼠相当。用抗VEGFR2抗体治疗消除了经治疗的1型糖尿病小鼠所显示的灌注恢复改善。在缺血的1型糖尿病后肢和暴露于模拟缺血的内皮细胞中，高血糖损害了VEGFR2表达，并与VEGFR2泛素化增加有关。抑制泛素-蛋白酶体复合物可恢复模拟缺血状态下内皮细胞VEGFR2的正常表达。
1型糖尿病中的高血糖损害缺血后肢的VEGFR2蛋白表达，可能是由于蛋白酶体复合物的泛素化和降解增加所致。血糖控制可使缺血状态下的VEGFR2水平正常化，并改善灌注恢复。
