It’s a heart-rending legacy: mothers who have uncontrolled diabetes during pregnancy are three times more likely to give birth to babies with malformed hearts than are mothers whose blood sugar levels are normal. Doctors have known that for some time, but recent work by researchers at Yale and the University of Arizona helps explain how high blood glucose levels in the mother lead to infant heart defects, and may suggest ways to prevent the problem.

“Lack of control of glucose in early pregnancy is a serious problem, because often the woman doesn’t even know she’s pregnant at the time,” said Joseph A. Madri, Ph.D., M.D., HS ’76, FW ’80, professor of pathology and co-director of medical studies. “Yet this period of the first few weeks is critical, because this is when formation of all the organs occurs.”

In earlier work, Madri and co-workers including Emese Pinter, M.D., an associate research scientist in pediatrics, studied the formation of blood vessels of the yolk sac in a mouse model of maternal diabetes. “We found that higher levels of glucose, comparable to what would be found in a diabetic mother, had profound effects on the development of yolk sac vasculature,” said Madri. “The vasculature of the yolk sac, which is important for nutrient, gas and waste exchange in the developing embryo, was arrested when the glucose level was high.” What’s more, glucose levels didn’t have to remain high for long to cause serious problems, the research showed. Even a brief spike could be enough to abort a pregnancy.

In the newer work, published in the February 17 issue of The Journal of Cell Biology, Madri, Pinter and co-workers focused on a slightly later stage of development, when the cardiovascular system begins to form. Normally, this is a multistep process involving the endocardial cushion, a small area in the embryonic heart with two tissue layers, the endocardium and the myocardium.

“For normal development, endocardial cells overlying the cushion area have to dissociate from one another and migrate into the tissue beneath the endocardium called the cardiac jelly,” said Madri. To investigate how the process is disrupted under high-glucose conditions, the researchers used an in vitro model of endocardial cushion formation. With this model, they showed that high glucose levels inhibit dissociation and migration of the endocardial cells and that this disruption occurs during a critical window at the developmental stage when the embryo consists of 20 to 25 somites (block-like segments of tissue). Next, they explored the role of a regulatory molecule that is involved in keeping the cells in a sheet-like layer. In normal development, levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) drop in the endocardial cells overlying the cushion area, allowing the endocardial cells to move apart and migrate into the cardiac jelly to form such structures as the valves and part of the walls between the chambers of the heart. But when glucose levels are elevated, PECAM-1 persists, the researchers found.

“The endocardial cells can’t dissociate from each other and migrate,” said Madri. “The result is a heart with an opening between chambers or one in which there are problems with the structure of the valves.”

Why does PECAM-1 persist when glucose levels are high? The research implicates vascular endothelial growth factor A (VEGF-A), known to be important in the development of new blood vessels and the regulation of associated processes. Typically in diabetic adults, VEGF-A levels rise along with glucose levels. But for reasons Madri, Pinter and co-workers don’t yet understand, in fetuses VEGF-A shows the opposite effect—its levels drop when glucose is high. Because VEGF-A affects the regulation of PECAM-1, low VEGF-A levels mean that PECAM-1 isn’t properly controlled, allowing it to overstay its welcome.

Now, said Madri, “we’re trying to understand how VEGF is controlled in the fetus and how that’s different than in the adult. Once we know this, perhaps we can devise modalities to blunt the effect of excess glucose in the fetus.”