Sascha Drewlo, Ph.D., assistant professor of obstetrics and gynecology for the Wayne State University School of Medicine, has secured a $1.25 million grant from the National Heart, Lung and Blood Institute of the National Institutes of Health to study the role of approved drugs to improve placental function.
The R01 grant (1R01HL128628) will fund Drewlo's research into the effectiveness of the drug rosiglitazone, sold as the diabetic medication Avandia, in stimulating a placental signaling channel to halt severe preeclampsia.
Drewlo is exploring a novel signaling pathway within the placenta that, when altered with rosiglitazone, can restore normal vascular function, preventing preeclampsia in pregnant mothers.
Preeclampsia, a sudden increase in blood pressure after the 20th week of pregnancy, is the leading cause of fetal and maternal death worldwide. Women not killed by preeclampsia can suffer lifelong health problems from the condition. Indicated by a sudden increase in blood pressure and protein in the urine, preeclampsia warning signs, in addition to elevated blood pressure, can include headaches, swelling in the face and hands, blurred vision, chest pain, and shortness of breath. While the condition can manifest within a few hours, some women report few or no symptoms.
The condition is responsible for 76,000 maternal deaths and more than 500,000 infant deaths annually, according to estimates from the Preeclampsia Foundation. The condition occurs only during pregnancy. Some mothers develop seizures (eclampsia) and suffer intracranial hemorrhage, the main cause of death in those who develop the disorder. The babies of preeclamptic mothers may develop intrauterine growth restriction or die in utero.
Severe preeclampsia, Drewlo explained, is believed to stem from the placenta since the only available "cure" is delivery of the fetus. In severe cases, early fetal delivery is necessary, leading to preterm birth, which carries a host of long-term complications for the infant.
At the molecular level, Peroxisome proliferator-activated receptor-gamma, or PPAR-γ, a transcription factor and a nuclear receptor, is primarily known for its role in lipid metabolism. Researchers have shown that PPAR-γ also regulates lineage differentiation in trophoblast stem cells in mice through the control of glial cell missing-1, or GCM-1, a protein-coding gene in the placenta. The trophoblast stem cells provide nutrients to the embryo and develop into a large portion of the placenta. The expression of GCM-1 has been shown to affect the formation of new blood vessels in embryos, which can result in preeclampsia.
Drewlo has found that when PPAR-γ in placental development in mice was stimulated by rosiglitazone, preeclampsia-like symptoms were reduced. At the same time, inhibiting PPAR-γ induced preeclampsia-like features. Rosiglitazone, in diabetics, binds PPAR receptors in fat cells, making them more responsive to insulin.
"We hypothesize that human trophoblast differentiation is regulated by the PPARγ - GCM1 axis, which can be pharmacologically activated to improve placental and, in turn, maternal endothelial function," Drewlo said. "The ultimate goal of the proposed research program is to improve pregnancy outcome by restoring placental and maternal vascular function in severe preeclampsia."
Drewlo said that in pregnancy, PPAR-γ oversees the release of factors that inhibit the growth of new blood vessels through a GCM-1-dependent pathway. Preliminary studies in human placental explants suggest that PPAR-γ directly controls trophoblast differentiation by regulating the expression of GCM-1. PPAR-γ activation with rosiglitazone significantly decreased the secretion of blood vessel growth inhibitors.
According to the Preeclampsia Foundation, the condition, also known as toxemia or pregnancy-induced hypertension, affects 5 to 8 percent of pregnancies. Approximately 13 percent of all maternal deaths worldwide - the death of a mother every 12 minutes - have been attributed to eclampsia. The foundation reports that preeclampsia is responsible for nearly 18 percent of all maternal deaths in the United States.
Even if treated successfully, preeclampsia can bring future health problems for mothers. Women who have had preeclampsia have double the risk for heart disease and stroke over the next five to 15 years after treatment. The condition can cause blindness in some mothers.
The Preeclampsia Foundation estimates that in the United States about 10,500 babies die annually as a result of preeclampsia. The cost of the condition in the U.S., according to the foundation, is $7 billion annually, split between $3 billion a year in treating mothers and $4 billion a year for the cost of treating infants born prematurely.
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