A Protein Tied to Pregnancy Disorder

Times Staff Writer

Boston researchers have discovered the elusive cause of preeclampsia, the sometimes fatal complication of pregnancy that affects about 200,000 U.S. women each year.

Studying pregnant women, a team from Beth Israel Deaconess Medical Center discovered that the disorder is associated with high levels of a protein that narrows blood vessels, impeding the flow of blood and oxygen.

When they then induced high levels of the protein in rats, the animals developed the symptoms of preeclampsia, Dr. S. Ananth Karumanchi and his colleagues reported in March's Journal of Clinical Investigation.

The discovery will allow rapid diagnosis of the problem and should lead to the first effective therapy for the disorder, experts said.

The discovery could provide "an amazing breakthrough," said Dr. Marshall Lindheimer of the University of Chicago. "Preeclampsia is a neglected disease that is finally having its day in court. That's important because the health burden is enormous."

More than 6 million women around the world suffer preeclampsia during pregnancy each year, and the rate appears to be growing. The disorder, once known as toxemia, has been generally thought to affect about 5% of pregnancies, but the National Institutes of Health recently reported the rate increased to about 8% during the 1990s.

The disorder, usually diagnosed late in pregnancy, is characterized by sharp increases in blood pressure, swelling and proteins in the urine. It can progress to eclampsia, which produces seizures and often fatal complications of the liver, kidneys, lungs, blood and nervous system. Eclampsia causes 15% of maternal deaths during pregnancy in the United States.

In mild cases of preeclampsia, the primary treatment is bed rest. In more severe cases, the infant is generally delivered by Caesarian section, whether the infant has reached term or not. A study this year suggested that infusions of magnesium sulfate also could ease symptoms, but that approach is not widely used.

Much research over the last decade has suggested that preeclampsia is caused by some factor released into the bloodstream by the placenta, but researchers had not been able to identify this agent.

Karumanchi and his colleagues used a new technique called gene expression profiling to determine which genes in the placental cells of pregnant women -- both with preeclampsia and without it -- were actively ordering the production of proteins. This technique "wasn't possible even two or three years ago," he said.

The only difference they observed between the two groups of women was the production of a previously known protein called soluble fms-like tyrosine kinase 1 (sFlt1), found in women with preeclampsia. This protein binds to two growth factors, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF).

By binding to the two growth factors, the protein should remove them from circulation. When the team reexamined the blood samples from the pregnant women with preeclampsia, they found there were reduced levels of VEGF and PlGF.

The team then exposed pregnant and non-pregnant rats to sFlt1 and observed that all of the animals developed symptoms of the disease, "demonstrating for the first time a clear cause-and-effect relationship between this protein and this disease," Karumanchi said.

Both VEGF and PlGF stimulate the growth of blood vessels, necessary for the growth of the fetus.

Both hormones also are necessary to maintain the health of small blood vessels that already have been formed. A lower-than-normal level of VEGF adversely affects the health of the mother's blood vessels and causes organ damage throughout the body.

In another paper in the same journal, a team from Mount Sinai Hospital in Toronto reported that mice genetically engineered to produce below-normal levels of VEGF developed kidney problems characteristic of preeclampsia.

The two reports "shed unprecedented light on the pathogenesis of preeclampsia and offer novel therapeutic opportunities for this disease," researchers from the Catholic University of Leuven in Belgium concluded in an editorial in the same journal.

The first obvious treatment would be to administer the growth factors to women with preeclampsia in an effort to "sop up" the excess sFlt1, Karumanchi said. Both growth factors already are being produced and administered to humans for other purposes, so they are known to be safe.

"We simply have to test the correct doses in animal models, then we can go into clinical trials in women with severe illness," he said.

In the longer term, it should be possible to identify drugs that would block production of excess sFlt1. One drug that has been shown to do this in the test tube is nicotine. Epidemiological studies, furthermore, show the rate of preeclampsia is lower among women who smoke.

Karumanchi emphasized, however, that researchers are not encouraging pregnant women to smoke because tobacco use produces a variety of adverse effects on the fetus.

Karumanchi and his colleagues are working with stored blood samples to determine whether high levels of the protein appear in blood before women develop symptoms of preeclampsia. If that proves to be the case, he said, it may be possible to intervene earlier in pregnancy to minimize problems.

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