Nature study shows that COMT levels were reduced in women with preeclampsia, and mice lacking the gene had more stillbirths.

Researchers found that the COMT gene plays a role in preeclampsia. The study further suggests that a steroid molecule, 2-ME, may serve as both a diagnostic marker and therapeutic supplement for the treatment of this dangerous pregnancy disorder.

During pregnancy, hypoxia is associated with the formation of new blood vessels. As the pregnancy progresses, hypoxia levels should naturally come down as fetal blood vessel formation slows, but for unknown reasons, patients with preeclampsia remain hypoxic well into their third trimester of pregnancy.

Knowing that placental hypoxia associated with vascular dysfunction is a hallmark of the condition, the researchers began by screening for genes that regulate hypoxia. They found that an enzyme known as COMT (catechol-O-methyltransferase) was involved in preeclampsia.

“Interestingly, this enzyme contributes to the breakdown of estrogen into 2-ME (2-methoxyestradiol), a metabolite that suppresses the activity of hypoxia inducible factor protein,” explains senior author Raghu Kalluri, Ph.D., chief of the division of matrix biology at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School. “We wondered if, in cases of preeclampsia, COMT was not functioning properly. In support of this hypothesis, we found that COMT levels were deficient and 2-ME levels were lower in pregnant women with preeclampsia.”

Next the investigators looked at genetically engineered COMT deficient mice. The animals failed to produce 2-ME. At 14 weeks gestation, they developed protein leak in the urine, high blood pressure, and problems with placental blood vessels associated with decreased oxygen levels. In addition, the animals delivered a day or so earlier than normal pregnant mice and there was a greater incidence of stillborn pups. Once the pups were delivered, however, the health of the mother returned to normal. In the final portion of the study, the authors administered 2-ME to the mice, resulting in a reversal of preeclampsia-like symptoms.

“Interestingly, the many diverse factors that have been identified in the recent years as elevated or suppressed in women with preeclampsia are fixed by 2-ME, suggesting that this action of COMT is central to proper vascular function in the placenta,” notes Dr. Kalluri. “

The study was published May 11 in the advance online issue of Nature.

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