Journal article
Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD
Cardiovascular research, Vol.101(3), pp.364-372
03/01/2014
DOI: 10.1093/cvr/cvt342
PMCID: PMC3928005
PMID: 24385342
Abstract
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.
Details
- Title: Subtitle
- Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD
- Creators
- Ayotunde O. Dokun - University of VirginiaLingdan Chen - University of VirginiaSwapnil S. Lanjewar - University of VirginiaRobert John Lye - University of VirginiaBrian H. Annex - University of Virginia
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.101(3), pp.364-372
- DOI
- 10.1093/cvr/cvt342
- PMID
- 24385342
- PMCID
- PMC3928005
- NLM abbreviation
- Cardiovasc Res
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Publisher
- Oxford Univ Press
- Number of pages
- 9
- Grant note
- Harold Amos Medical Faculty Development Program award 3 R01 HL101200-01S1 / NIH/NHBLI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL101200 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Robert Wood Johnson Foundation; Robert Wood Johnson Foundation (RWJF)
- Language
- English
- Date published
- 03/01/2014
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984297600102771
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