Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic rats
Article first published online: 1 DEC 2004
Copyright © 2004 Wiley-Liss, Inc.
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume 70, Issue 12, pages 927–938, December 2004
How to Cite
Molin, D. G.M., Roest, P. A.M., Nordstrand, H., Wisse, L. J., Poelmann, R. E., Eriksson, U. J. and Gittenberger-De Groot, A. C. (2004), Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic rats. Birth Defects Research Part A: Clinical and Molecular Teratology, 70: 927–938. doi: 10.1002/bdra.20101
- Issue published online: 9 DEC 2004
- Article first published online: 1 DEC 2004
- Manuscript Accepted: 5 OCT 2004
- Manuscript Received: 24 AUG 2004
- Netherlands Heart Foundation. Grant Number: NHS46.014
- tetralogy of Fallot;
- aortic arch;
Maternal diabetes (MD) is a risk factor for offspring to develop cardiovascular anomalies; this is of growing clinical concern since the number of women in childbearing age with compromised glucose homeostasis is increasing. Hyperglycemia abrogates cardiovascular development in vitro; however, a link to cardiovascular defects in diabetic offspring remains to be investigated.
We have studied cardiovascular development in offspring of MD rats by examining serial histological sections of GD 12.0–18.0 offspring. Development of pharyngeal arch artery malformations was analyzed and related to intracardiac anomalies.
Pharyngeal arch artery and intracardiac defects were present in 27 of 37 MD GD 13.0–18.0 offspring. Early sixth arch arteries showed abrogated arteriogenesis, whereas fourth arch artery defects developed as a result of abnormal remodeling. Morphometrical analysis showed increased apoptosis in regressing artery segments and reduced apoptosis in persisting artery segments. Double outlet right ventricle with infundibular stenosis (tetralogy of Fallot) was predominantly found in combination with sixth artery defects and pulmonary atresia. As confirmed by morphometric analysis and three-dimensional (3D)-reconstructions, outflow tract defects coincided with endocardial cushion hypoplasia. Cases with teratology of Fallot additionally showed a shorter outflow tract. No relation with apoptosis or disturbed neural crest cell migration was found.
Our data uniquely demonstrate mechanistic differences involved in the development of sixth and fourth artery anomalies. Whereas increased apoptosis induces fourth artery anomalies, pulmonary outflow obstruction abrogates sixth artery differentiation independent of apoptosis. The model presented allows analysis of diabetic conditions on cardiovascular development in vivo, essential for elucidating this teratology. Birth Defects Research (Part A), 2004. © 2004 Wiley-Liss, Inc.