These findings, which could help lead to the development of diagnostic tools and therapies for this baffling condition, appear in the March 2003 issue of The Journal of Clinical Investigation.
Also known as toxemia, preeclampsia occurs in an estimated 5 percent of all pregnancies, affecting approximately 200,000 women in the U.S. each year. The condition typically develops after the 20th week of pregnancy and in mild cases, is characterized by high blood pressure, edema, and protein in the urine. In severe cases, the condition can rapidly develop into eclampsia, in which the mother suffers serious - and potentially fatal - seizures.
"Currently, there is no treatment for this condition," says the study's lead author S. Ananth Karumanchi, M.D., of the Renal Division at BIDMC and Instructor of Medicine at Harvard Medical School. "The only management we can offer patients is to deliver the baby and the placenta, which can result in the infant being born prematurely." As a result, preeclampsia is one of the leading causes of maternal and infant mortality in developing countries.
In a normal pregnancy, the developing fetus signals the mother's body to widen blood vessels to the placenta, which supplies oxygen and nutrients to the fetus. But, for unknown reasons, in women with preeclampsia the blood vessels grow narrower, impeding the flow of blood and oxygen. The diminished oxygen levels apparently set in motion a rapid progression of potentially fatal complications involving the mother's liver, kidneys, lungs, blood and nervous system.
Scientists have long speculated that the placenta was releasing some unknown factor that was triggering this abnormal course of events. In order to identify this factor, Karumanchi and his colleagues first performed gene expression profiling tests of placental tissue from patients with and without preeclampsia.
The test results showed that a protein known as soluble fms-like tyrosine kinase 1 (sFlt1) was significantly elevated among the preeclampsia patients. With this information in hand, the researchers administered the protein to both pregnant and non-pregnant rats to test whether sFlt1 was at the root of the problem.
"The resulting data was exciting," says Karumanchi. "The rats that were exposed to sFlt1 had distinct clinical and pathological symptoms of preeclampsia, demonstrating for the first time a clear cause and effect relationship between this protein and this disease."
What is apparently happening, he explains, is that sFlt1 is binding to and "mopping up" another group of proteins, known as angiogenic factors. "Vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) exist to promote angiogenesis, the growth and health of small blood vessels," he explains. VEGF has, in fact, been shown to promote tumor growth among cancer patients and is therefore the target of anti-angiogenic therapies being developed for the treatment of some malignancies.
Among preeclampsia patients, says Karumanchi, the diminished levels of VEGF and PIGF caused by the actions of sFlt1 affect the health of the mother's small blood vessels, and ultimately lead to the telltale symptoms of preeclampsia.
"These findings provide us with an important piece of information as we work to develop strategies to treat preeclampsia," notes Karumanchi. "We're obviously a number of years away from being able to put these to use in humans but these results are an important step in the process." Furthermore, adds study coauthor Vikas Sukhatme, M.D., Ph.D., this study has important implications for the use of anti-angiogenic therapies in the treatment of cancer.
Study coauthors include Sharon Maynard, M.D., Jiang-Yong Min, M.D., Jaime Merchan, M.D., Kee-Hak Lim, M.D., Jianyi Li, Ph.D., Susanta Mondal, Ph.D., Towia Libermann, Ph.D., James Morgan, M.D., Ph.D., Frank Sellke, M.D., Isaac Stillman, M.D., Franklin Epstein, M.D., and Vikas Sukhatme, M.D., Ph.D., who represent the Departments of Medicine, Surgery, Pathology and Obstetrics and Gynecology at Beth Israel Deaconess Medical Center.
The study was supported by grants from the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Society of Nephrology, and support from Beth Israel Deaconess Medical Center.
Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. The Department of Obstetrics and Gynecology at BIDMC delivers 5,000 infants each year and specializes in the care of high-risk pregnant women, including preeclampsia patients. Beth Israel Deaconess is the third largest recipient of National Institutes of Health funding among independent U.S. teaching hospitals.