Women with pregestational diabetes have a 3-5 times increased risk of giving birth to malformed babies compared with non-diabetic women. The malformations are likely to be induced before the seventh week of pregnancy, when the yolk sac is partly responsible for the transfer of metabolites to the embryo, and the uterine blood flow to the implantation site determines the net amount of nutrients available to the conceptus. We aimed to evaluate the effect on embryogenesis caused by a diabetes-induced disturbance in either yolk sac morphology or uterine blood flow.
We examined the extent to which maternal diabetes with or without folic acid (FA) supplementation affects mRNA levels and protein distribution of ROS scavenging enzymes (SOD, CAT, GPX), vascular endothelial growth factor-A (Vegf-A), folate binding protein-1 (Folbp-1), and apoptosis associated proteins (Bax, Bcl-2, Caspase-3) in the yolk sacs of rat embryos on gestational ages 10 and 11. We found that maternal diabetes impairs vascular morphology and decreases CuZnSOD and Gpx-1 gene expression, increases the levels of CuZnSOD protein, increases the Bax/Bcl-2 protein ratio and decreases Vegf-A protein distribution in yolk sacs. FA treatment normalizes vascular morphology, decreases mRNA levels of all three SOD isoforms and increases Vegf-A mRNA levels, rectifies CuZnSOD protein distribution and Bax/Bcl-2 ratio.
We conclude that a teratogenic diabetic environment produces a state of vasculopathy, oxidative stress, and mild apoptosis in the yolk sac. FA administration normalizes vascular morphology, diminishes apoptotic rate, and increases Vegf-A gene expression and protein distribution in the yolk sac of diabetic rats.
The blood flow to implantation sites was estimated with a laser doppler flow meter in normal and diabetic pregnant rats on gestational days 9, 11, 13, and 15. Maternal diabetes causes increased blood flow to implantation sites compared with normal pregnancy. Malformed offspring of diabetic rats show impaired growth and decreased blood flow compared with their littermates at all gestational days. Resorbed offspring display increased blood flow compared with their non-resorbed littermates. Maternal diabetes causes decreased gene expression of CuZnSOD, MnSOD and Gpx-1, increased Bax/Bcl-2 ratio, and increased Vegf-A expression in the offspring at all gestational days, as well as increased p53 expression in the GD13 and GD15 offspring.
In conclusion, both maternal metabolism and embryonic developmental state affect the blood flow to the implantation site. Maternal diabetes causes decreased anti-oxidative capacity, enhanced apoptosis and angiogenesis in the offspring.
Biomedicum,Uppsala , 2007.
Diabetes, yolk sac, embryo, gene expression, blood flow, folic acid, SOD, apoptosis