Mouse Model for Preeclampsia Discovered

Contact: Jennifer BrownHealth Science RelationsUniversity of Iowa(319) 335-9917[email protected]

Feb. 19, 2002

IOWA CITY, Iowa -- Using new technology to monitor blood pressure, University of Iowa scientists and their colleagues have discovered that a lab-bred mouse with borderline hypertension (high blood pressure) may be a very good model for studying preeclampsia in women.

Preeclampsia is a serious disease associated with pregnancy. It is the leading cause of death in pregnant women and affects between 5 and 15 percent of all pregnancies. Preeclampsia also is associated with a high risk of death and disease for fetuses, which are often abnormally small. If left untreated, preeclampsia progresses to eclampsia, a condition characterized by convulsions, which can result in coma or death. The only way to prevent the progression of preeclampsia to eclampsia is to deliver the baby and the placenta. Once the baby is delivered, the mother seems to completely recover.

The UI team believes that studies using the new mouse model will improve understanding of preeclampsia, and could lead to useful interventions and treatments for women with the condition. The study appears in the February supplemental issue of the journal Hypertension.

"This syndrome was described by the ancient Egyptians, so it's something we've known about for a long time but we've never known what causes it," said Robin L. Davisson, Ph.D., UI associate professor of anatomy and cell biology. "One of the reasons we don't understand preeclampsia is that there haven't been any animal models that accurately mimic the disease that we see in humans."

Women with preeclampsia develop hypertension during the third trimester of the pregnancy and excrete increased levels of protein in their urine (proteinuria), which is a sign of kidney problems.

Population studies have shown that borderline hypertension, or a slightly higher than normal blood pressure, is one risk factor for women who develop preeclampsia. This fact caused Davisson and her colleagues to take a fresh look at a particular strain of lab-bred mouse that had been developed by cross breeding several decades ago. These mice have slightly elevated blood pressure at rest and in that respect are similar to women who are at risk of developing preeclampsia.

"We set out to see if the mice would develop something that resembles preeclampsia during pregnancy," Davisson said. "But in order to do the necessary experiments, we needed to be able to monitor blood pressure in a pregnant mouse for the entire duration of the pregnancy and beyond delivery."

To accomplish this technically challenging goal, the UI team developed a new system based on a technique called radiotelemetry. A tiny radio transmitter is implanted into the mouse. The transmitter is connected to a small fluid-filled tube placed in the mouse's blood vessel. Blood flowing past the tube generates a signal, which is sent by the transmitter to an external receiver. The signal is used to accurately measure heart rate and blood pressure, which can be recorded for 10 seconds every five minutes, 24 hours a day, over the course of the entire pregnancy and the postpartum period. The transmitter can be turned on and off with a magnet. The device allows blood pressure to be closely monitored in a way that is non-invasive and stress-free for the mice.

"An implanted mouse appears to be entirely unaware of the device," Davisson said. "It has free run of its home cage and our studies show that it lives and breeds as happily as a non-implanted mouse."

The researchers implanted the radiotelemetry device into non-pregnant mice and recorded blood pressure before the mice became pregnant to get a good measure of the animals' baseline blood pressure. The mice were then allowed to breed and the researchers kept track of blood pressure changes over the course of pregnancy including the postpartum period. Pregnancy lasts for three weeks in a mouse.

The researchers found that these mice experience a significant increase in blood pressure during the last trimester (week three) of pregnancy and that this high blood pressure drops back to baseline after the babies are delivered. The studies also showed that the levels of protein in the urine of the mice increased during the last trimester of pregnancy and went back to normal after delivery of the pups.

Both the blood pressure pattern and the proteinuria precisely mirror the changes that occur in women with preeclampsia. In contrast to other animal models previously developed to study preeclampsia, Davisson and her colleagues have shown that this mouse model very accurately mimics the clinical signs and symptoms of the human disease.

"We are very excited because for the first time we have an opportunity with this mouse to really investigate what is going on in preeclampsia in a systematic, experimental way," Davisson said.

In addition to the increased blood pressure and the proteinuria, the mice also appear to develop other characteristic symptoms of preeclampsia including kidney disease and problems in the lining of blood vessels.

Preeclampsia almost certainly has a genetic component, although like most complex diseases both genetic and environmental factors are likely to play a role.

"We know so much about mouse genetics that we can bring those tools to bear on our questions. Also, we can very precisely manipulate the genome of the mouse and look directly at the outcome any genetic manipulation has on the disease," Davisson said. "The whole idea is to use this model to understand the molecular basis of the disease."

The UI team used a special ultrasound to study the fate of the fetuses in the mouse model over the course of pregnancy. The researchers found that early pregnancy looked normal with the usual number of fetuses. However, as the pregnancy progressed some fetuses were lost. Interestingly, this demise of the pups started to happen before the clinical signs of rising blood pressure and proteinuria.

"The observation that things are going wrong before the mother's health problems occur is a new finding," Davisson said. "We've never been able to study the disease this closely before."

This finding may lend weight to the hypothesis that some defect in the maternal-fetal interaction is the underlying cause of the disease. The team plans to use their new mouse model to further investigate this hypothesis.

In addition to Davisson, the UI researchers included Darren S. Hoffmann, Ph.D., Genelle M. Butz, Gilbert Aldape, James N. Bates, M.D., Ph.D., associate professor of anesthesia, Sanjeev Sethi, M.D., assistant professor of pathology, and Robert M. Weiss, M.D., associate professor of internal medicine and director of cardiovascular programs at the Veterans Affairs Medical Center, Iowa City. David C. Merrill, M.D., Ph.D., associate professor of maternal-fetal medicine at Wake Forest School of Medicine, and Gunther Schlager, Ph.D., professor emeritus of biological sciences at University of Kansas who first bred this particular strain of mice, also were part of the research team.

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