Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD

Ayotunde Dokun, Lingdan Chen, Swapnil S. Lanjewar, Robert John Lye, Brian H. Annex

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

AimsDiabetes 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 resultsHind 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.ConclusionHyperglycaemia 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.

Original languageEnglish (US)
Pages (from-to)364-372
Number of pages9
JournalCardiovascular research
Volume101
Issue number3
DOIs
StatePublished - Mar 1 2014

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Vascular Endothelial Growth Factor Receptor-2
Peripheral Arterial Disease
Perfusion
Ischemia
Proteins
Extremities
Ubiquitination
Proteasome Endopeptidase Complex
Ubiquitin
Hyperglycemia
Lower Extremity
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD. / Dokun, Ayotunde; Chen, Lingdan; Lanjewar, Swapnil S.; Lye, Robert John; Annex, Brian H.

In: Cardiovascular research, Vol. 101, No. 3, 01.03.2014, p. 364-372.

Research output: Contribution to journalArticle

Dokun, Ayotunde ; Chen, Lingdan ; Lanjewar, Swapnil S. ; Lye, Robert John ; Annex, Brian H. / Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD. In: Cardiovascular research. 2014 ; Vol. 101, No. 3. pp. 364-372.
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N2 - AimsDiabetes 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 resultsHind 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.ConclusionHyperglycaemia 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.

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