title: Specific local cardiovascular changes of Nepsilon-(carboxymethyl)lysine, vascular endothelial growth factor, and Smad2 in the developing embryos coincide with maternal diabetes-induced congenital heart defects.
abstract: OBJECTIVE
  Embryos exposed to a diabetic environment in utero have an increased risk to develop congenital heart malformations. The mechanism behind the teratogenicity of diabetes still remains enigmatic. Detrimental effects of glycation products in diabetic patients have been well documented. We therefore studied a possible link between glycation products and the development of congenital cardiovascular malformations. Furthermore, we investigated other possible mechanisms involved in this pathogenesis: alterations in the levels of vascular endothelial growth factor (VEGF) or phosphorylated Smad2 (the latter can be induced by both glycation products and VEGF).
  
  
  METHODS
  We examined the temporal spatial patterning of the glycation products Nepsilon(carboxymethyl)lysine (CML) and methylglyoxal (MG) adducts, VEGF expression, and phosphorylated Smad2 during cardiovascular development in embryos from normal and diabetic rats.
  
  
  RESULTS
  Maternal diabetes increased the CML accumulation in the areas susceptible to diabetes-induced congenital heart disease, including the outflow tract of the heart and the aortic arch. No MG adducts could be detected, suggesting that CML is more likely to be indicative for increased oxidative stress than for glycation. An increase of CML in the outflow tract of the heart was accompanied by an increase in phosphorylated Smad2, unrelated to VEGF. VEGF showed a time-specific decrease in the outflow tract of embryos from diabetic dams.
  
  
  CONCLUSIONS
  From our results, we can conclude that maternal diabetes results in transient and localized alterations in CML, VEGF expression, and Smad2 phosphorylation overlapping with those regions of the developing heart that are most sensitive to diabetes-induced congenital heart disease.
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Pauline A M
authors.initials: PA
authors.lastname: Roest
authors.forename: Daniël G M
authors.initials: DG
authors.lastname: Molin
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Iperen
authors.forename: Parri
authors.initials: P
authors.lastname: Wentzel
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Eriksson
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000453:epidemiology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000473:pathology; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D051899:Smad2 Protein / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics
chemical_list: D017127:Glycation End Products, Advanced; D051899:Smad2 Protein; D042461:Vascular Endothelial Growth Factor A; C048496:N(6)-carboxymethyllysine; D008239:Lysine