Cardiac malformations and alteration of TGFbeta signaling system in diabetic embryopathy

Birth Defects Res B Dev Reprod Toxicol. 2010 Apr;89(2):97-105. doi: 10.1002/bdrb.20225.


Background: Cardiovascular defects are the most common anomalies in diabetic embryopathy. The mechanisms underlying the manifestation of the defects remain to be addressed.

Methods: Female mice were administered streptozotocin to induce diabetes. Embryos from euglycemic (control) and hyperglycemic groups were examined for morphological and histological evaluation of malformations. Cell proliferation and programmed cell death (apoptosis) were assessed using mitotic markers (BrdU and Ki67) and TUNEL assay, respectively. Expression of eight four genes in the TGFbeta signaling system was analyzed using real-time RT-PCR.

Results: Structural abnormalities were observed in the heart and neural tube in diabetic groups, with significantly higher malformation rates than in control groups. Moreover, malformation rates in the heart were higher than those in the neural tube. Cardiac abnormalities including dilated heart tube, smaller ventricles, conotruncal stenosis, and abnormal heart looping were seen during early morphogenesis prior to cardiac septation [embryonic day (E) 9.5-11.5]. Histological examinations showed hypoplastic myocardium and endocardial cushions. After cardiac septation (E15.5), ventricular septal defects were observed, which were manifested in the non-muscular portion of the septum. Significant decreases in cell proliferation with no differences in apoptosis were observed in the myocardium and endocardial cushions in diabetic compared to control groups. Factors in the TGFbeta signaling that regulate heart development were downregulated by maternal diabetes.

Conclusions: Maternal diabetes causes malformations in the heart of the embryo. The heart is more susceptible to maternal diabetic insults than the neural tube. Malformations in the heart prior to septation are associated with decreased cell proliferation, but not increased apoptosis. The TGFbeta signaling is involved in cardiac malformations in diabetic embryopathy.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology*
  • Down-Regulation
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / embryology
  • Embryonic Development / drug effects
  • Embryonic Development / genetics
  • Female
  • Gene Expression Regulation, Developmental
  • Heart / drug effects
  • Heart / embryology*
  • Heart Defects, Congenital / chemically induced
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / metabolism*
  • Mice
  • Myocardium / metabolism
  • Myocardium / pathology
  • Pregnancy
  • Pregnancy in Diabetics*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*


  • Transforming Growth Factor beta