title: Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD.
abstract: OBJECTIVE
  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.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, VA 22901, USA.
authors.forename: Ayotunde O
authors.initials: AO
authors.lastname: Dokun
authors.forename: Lingdan
authors.initials: L
authors.lastname: Chen
authors.forename: Swapnil S
authors.initials: SS
authors.lastname: Lanjewar
authors.forename: Robert John
authors.initials: RJ
authors.lastname: Lye
authors.forename: Brian H
authors.initials: BH
authors.lastname: Annex
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D010477:Perfusion / Q000379:methods; D058729:Peripheral Arterial Disease / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Diabetes; Glycaemic control; Hyperglycaemia; Peripheral arterial disease; Proteasome; VEGF receptor