High tissue glucose alters intersomitic blood vessels in zebrafish via methylglyoxal targeting the VEGF receptor signalling cascade

  1. Jens Kroll1,2,#
  1. 1Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  2. 2Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
  3. 35th Medical Department, Medical Faculty Mannheim, Heidelberg University
  4. 4Department of Medicine I and Clinical Chemistry, Heidelberg University and
  5. 5Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  1. #Corresponding Author: Jens Kroll, Email: jens.kroll{at}medma.uni-heidelberg.de

Abstract

Hyperglycemia causes micro- and macrovascular complications in diabetic patients. Elevated glucose (gluc) concentrations lead to increased formation of the highly reactive dicarbonyl methylglyoxal (MG); yet, the early consequences of MG for development of vascular complications in vivo is poorly understood. In this study zebrafish was used as a model organism to analyze early vascular effects and mechanisms of MG in vivo. High tissue glucose increased MG concentrations in tg(fli:EGFP) zebrafish embryos and rapidly induced several additional malformed and uncoordinated blood vessel structures that originated out of existing intersomitic blood vessels. However, larger blood vessels including the dorsal aorta and common cardinal vein were not affected. Expression silencing of MG degrading enzyme glyoxalase 1 (glo1) elevated MG concentrations and induced a similar vascular hyperbranching phenotype in zebrafish. MG enhanced phosphorylation of VEGF receptor 2 and its downstream target Akt/PKB. Pharmacological inhibitors for VEGF receptor 2 and Akt/PKB as well as MG scavenger aminoguanidine and glo1 activation prevented MG induced hyperbranching of intersomitic blood vessels. Taken together, MG acts on smaller blood vessels in zebrafish via the VEGF receptor signalling cascade, thereby describing a new mechanism that can explain vascular complications under hyperglycemia and elevated MG concentrations.

Footnotes

  • * Kristina Jörgens and Sandra J. Stoll contributed equally to this work.

  • Received March 3, 2014.
  • Accepted July 28, 2014.
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