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The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues.

Authors
  • Thangarajah, Hariharan
  • Yao, Dachun
  • Chang, Edward I
  • Shi, Yubin
  • Jazayeri, Leila
  • Vial, Ivan N
  • Galiano, Robert D
  • Du, Xue-Liang
  • Grogan, Raymon
  • Galvez, Michael G
  • Januszyk, Michael
  • Brownlee, Michael
  • Gurtner, Geoffrey C
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Aug 11, 2009
Volume
106
Issue
32
Pages
13505–13510
Identifiers
DOI: 10.1073/pnas.0906670106
PMID: 19666581
Source
Medline
License
Unknown

Abstract

Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1alpha functional activity was specifically caused by impaired HIF-1alpha binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1alpha/p300 interaction and transactivation by HIF-1alpha. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention.

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