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June 4, 2006

Researchers identify potential prognostic marker for preeclampsia

TORONTO — Researchers at Harvard Medical School and The Hospital for Sick Children (SickKids) have found a protein that contributes to the pathogenesis of preeclampsia, a common problem during pregnancy. This research was reported in the June 4, 2006 online advance issue of the journal Nature Medicine.

Preeclampsia occurs only during pregnancy and the period after birth. It affects both the mother and the unborn baby and has an incidence of at least five to eight per cent of all pregnancies. It is characterized by high blood pressure and the presence of protein in the urine.

This condition affects up to one in seven pregnant women around the world. Along with other hypertensive pregnancy disorders, preeclampsia is a leading cause of maternal and infant illness and death. While most women with preeclampsia go on to deliver healthy babies, it is a leading cause of preterm birth. What is largely been unknown is what causes the condition to develop.

“We previously discovered that sFlt1, a circulating anti-angiogenic protein made by the placenta, contributed to preeclampsia, but we knew that there were more of these types of proteins involved in the pathogenesis of preeclampsia since this is a very heterogeneous disease,” said Dr. Ananth Karumanchi, study principal investigator, nephrologist at the Beth Israel Deaconess Medical Center and assistant professor of Medicine, Obstetrics and Gynecology at Harvard Medical School. “Preeclampsia is a maternal hypertensive disorder caused by the placenta, so it made sense to look for factors that were related to the maintenance of health of blood vessels.”

When examining the placentas from preeclamptic mothers, the researchers found an increased amount of a protein called endoglin, known to be important in controlling the growth of blood vessels and which was particularly dramatic in the most severe forms of preeclampsia such as those with HELLP syndrome (a subtype of preeclampsia in which patients have liver failure and clotting problems) or preeclamptic patients with fetal growth restriction.

Endoglin was cloned and sequenced in the laboratory of SickKids researcher Dr. Michelle Letarte 20 years ago. This protein is found to be highly expressed in all types of blood vessels. Dr. Letarte’s group has been studying the role of this protein in the vascular system and how mutations in this gene lead to a disease called hereditary hemorrhagic telangiectasia.

“During pregnancy, endoglin is secreted from the placenta into the blood” said Dr. Letarte, study collaborator, senior scientist at SickKids and professor of Immunology, Medical Biophysics, Obstetrics/Gynecology & Paediatrics at the University of Toronto. “However, the discovery that soluble endoglin is present at much higher levels in the blood of pregnant women with preeclampsia means we can now explore it as a potential prognostic marker to identify the condition early in the pregnancy.”

This study also provides the first evidence that a well-known multifunctional growth factor, called transforming growth factor beta, normally regulates vascular health through the production of nitric oxide. Soluble endoglin interferes with this important mechanism.

The next step for the Harvard and SickKids teams is to characterize the endoglin protein produced by the placenta and determine how it can cause an increase in blood pressure in the mother. In the Nature Medicine paper, the authors have shown that soluble endoglin interferes with the production of a strong dilator of blood vessels known as nitric oxide. This reduction in nitric oxide increases blood pressure.

“Nitric oxide is necessary for normal cardiovascular health,” said Dr. Mourad Toporsian, one of the study’s lead authors and a postdoctoral fellow at Dr. Letarte’s lab at SickKids. “Our finding that soluble endoglin can affect the production of nitric oxide suggests that it may also be implicated in other cardiovascular or hypertensive disorders.”

The research teams will also further explore the mechanisms whereby soluble endoglin affects vascular health. They hope that this will eventually lead to the development of future therapy.

This research was supported by the National Institutes of Health, the Heart and Stroke Foundation of Ontario and SickKids Foundation.

SickKids Foundation is the largest non-governmental granting agency in child health in Canada. Established in 1972, the Foundation has granted over $500 million to The Hospital for Sick Children and over $65 million to researchers across the country. The mission of the Foundation is to inspire our communities to invest in health and scientific advances to improve the lives of children and their families across Canada and around the world. If you would like to make more research possible at SickKids, please make a donation.

Other members of the research team included Shivalingappa Venkatesha, Chum Lam, Jun-Chi Hanai, Tadanori Mammoto, Yuval Bdolah, Kee-Hak Lim, Hai-Tao Yuan, Towia Libermann, Issac Stillman, Franklin Epstein, Frank Sellke, Vikas Sukhatme, Drucilla Roberts and Patricia D. Amore of Harvard Medical School, as well as Yeon Kim and Roberto Romero of Wayne State University School of Medicine.

The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada’s most research-intensive hospital and the largest centre dedicated to improving children’s health in the country. As innovators in child health, SickKids improves the health of children by integrating care, research and teaching. Our mission is to provide the best in complex and specialized care by creating scientific and clinical advancements, sharing our knowledge and expertise and championing the development of an accessible, comprehensive and sustainable child health system. For more information, please visit www.sickkids.ca. SickKids is committed to healthier children for a better world. Donate to SickKids!

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