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First published online September 29, 2008
Experimental Biology and Medicine 233:1421-1432 (2008)
doi: 10.3181/0806-RM-186
© 2008 by the Society for Experimental Biology and Medicine
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ORIGINAL RESEARCH ARTICLE

Cardiac Malformations Are Associated with Altered Expression of Vascular Endothelial Growth Factor and Endothelial Nitric Oxide Synthase Genes in Embryos of Diabetic Mice

Srinivasan Dinesh Kumar, Sook-Kwin Yong, S. Thameem Dheen, Boon-Huat Bay and Samuel Sam-Wah Tay1

Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore 117597

To whom requests for reprints should be addressed at 1 Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, MD10, 4 Medical Drive, Singapore 117597, Singapore. E-mail: anttaysw{at}nus.edu.sg

The aim of this study was to investigate the role of nitric oxide (NO), and the expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) genes in developing hearts at embryonic day 13.5 of embryos from diabetic mice. The protein and mRNA expression levels of eNOS and VEGF were significantly altered in the developing hearts of embryos from diabetic mice. The NO level was significantly decreased, whereas the VEGF concentration was significantly increased in the developing hearts of the embryos from diabetic mice. In vitro study showed a significant reduction in eNOS expression and cell proliferation in cardiac myoblast cells exposed to high glucose concentrations. Further, high glucose induced apoptosis in myoblast cells. Ultrastructural changes characteristics of apoptosis, including cell blebbing, aggregation of ribosomes and vacuoles in the cytoplasm were also evident in myoblast cells exposed to high glucose. It is suggested that hyperglycemia alters the expression of eNOS and VEGF genes that are involved in the regulation of cell growth and vasculogenesis, thereby contributing to the cardiac malformations seen in embryos from diabetic mice.

Key Words: maternal diabetes • developing heart • H9C2 cell line • VEGF • eNOS • mice






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