Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD
Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD
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DOI：
10.1093/cvr/cvt342
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发表时间：
2014-03-01
影响因子：
10.8
通讯作者：
Annex, Brian H.
中科院分区：
文献类型：
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作者：
Dokun, Ayotunde O.;Chen, Lingdan;Annex, Brian H.
目的糖尿病(DM)在人类外周动脉疾病(PAD)和临床前PAD模型中与不良的临床结局相关，但对血糖控制的影响尚不清楚。观察血糖控制对1型糖尿病小鼠实验性PAD的影响，并探讨高血糖对小鼠缺血后血管内皮生长因子受体2(VEGFR2)表达的影响。方法与结果非糖尿病、未治疗和治疗的1型糖尿病小鼠均可诱发后肢缺血。我们评估了缺血后肢的血流恢复、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周表现出血流恢复受损，后肢毛细血管密度降低，缺血后第3天后肢VEGFR2蛋白表达降低。在相同的时间点，治疗的1型糖尿病小鼠的血流灌注恢复率、毛细血管密度和VEGFR2蛋白水平与非糖尿病小鼠相当。抗VEGFR2抗体治疗否定了接受治疗的1型糖尿病小鼠表现出的改善血流灌注恢复。在缺血型1型糖尿病后肢和暴露于模拟缺血的内皮细胞中，高糖损害了VEGFR2的表达，并与VEGFR2泛素化增加有关。抑制泛素-蛋白酶体复合体可恢复模拟脑缺血后血管内皮细胞VEGFR2的正常表达。结论1型糖尿病高血糖损伤缺血后肢VEGFR2蛋白的表达，可能是由于蛋白酶体复合体泛素化和降解增加所致。血糖控制可以使缺血时VEGFR2水平正常，并改善血流灌注恢复。
Aims 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.Methods and results 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 timepoints. 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.Conclusion 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.