title: High tissue glucose alters intersomitic blood vessels in zebrafish via methylglyoxal targeting the VEGF receptor signaling cascade.
abstract: Hyperglycemia causes micro- and macrovascular complications in diabetic patients. Elevated glucose 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 are poorly understood. In this study, zebrafish were 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 (ISVs). However, larger blood vessels, including the dorsal aorta and common cardinal vein, were not affected. Expression silencing of MG-degrading enzyme glyoxalase (glo) 1 elevated MG concentrations and induced a similar vascular hyperbranching phenotype in zebrafish. MG enhanced phosphorylation of vascular endothelial growth factor (VEGF) receptor 2 and its downstream target Akt/protein kinase B (PKB). Pharmacological inhibitors for VEGF receptor 2 and Akt/PKB as well as MG scavenger aminoguanidine and glo1 activation prevented MG-induced hyperbranching of ISVs. Taken together, MG acts on smaller blood vessels in zebrafish via the VEGF receptor signaling cascade, thereby describing a new mechanism that can explain vascular complications under hyperglycemia and elevated MG concentrations.
authors.affiliation: Department of Vascular Biology and Tumor Angiogenesis, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Jörgens
authors.affiliation: Department of Vascular Biology and Tumor Angiogenesis, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Stoll
authors.affiliation: Department of Vascular Biology and Tumor Angiogenesis, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany 5th Medical Department, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pohl
authors.affiliation: Department of Medicine and Clinical Chemistry, Heidelberg University, Mannheim, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fleming
authors.affiliation: Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Department of Medicine and Clinical Chemistry, Heidelberg University, Mannheim, Germany.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.affiliation: 5th Medical Department, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.affiliation: Department of Vascular Biology and Tumor Angiogenesis, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany jens.kroll@medma.uni-heidelberg.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000002:abnormalities / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011765:Pyruvaldehyde; D040301:Vascular Endothelial Growth Factor Receptor-2; C000595917:kdr protein, zebrafish; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose