Specific Local Cardiovascular Changes of Nɛ-(Carboxymethyl)lysine, Vascular Endothelial Growth Factor, and Smad2 in the Developing Embryos Coincide With Maternal Diabetes–Induced Congenital Heart Defects

doi:10.2337/db07-1016

Specific Local Cardiovascular Changes of N^ɛ-(Carboxymethyl)lysine, Vascular Endothelial Growth Factor, and Smad2 in the Developing Embryos Coincide With Maternal Diabetes–Induced Congenital Heart Defects

¹Department of Anatomy and Embryology, Leiden University Medical Centre, Leiden, the Netherlands;
²Department of Vascular Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands;
³Department of Internal Medicine, Maastricht University, Maastricht, the Netherlands; and
⁴Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.

Corresponding author: Adriana C. Gittenberger-de Groot, acgitten{at}lumc.nl.

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).

RESEARCH DESIGN AND METHODS We examined the temporal spatial patterning of the glycation products N^ε(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.

Footnotes

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- Received July 23, 2007.
- Accepted January 26, 2009.
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