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MATERNAL MEDICINE Protein Implicated In Life-threatening Pregnancy Complication Inhibition of Blood Vessel Growth May Lead to Preeclampsia Preeclampsia, a complication of pregnancy characterized by hypertension, edema, and protein in the urine, afflicts five to eight percent of pregnant women and is the leading cause of maternal death worldwide. Because it often compels premature delivery to save the mother, it is also a major cause of infant mortality in developing countries. The discovery by a team of researchers at HMS and Beth Israel Deaconess Medical Center of the protein that causes preeclampsia--a common complication of pregnancy that can lead to both maternal and infant mortality--may pave the way for early diagnosis and treatment of the condition. Standing (l to r): Kee-hak Lim, Towia Libermann, Vikas Sukhatme, Jaime Merchan, Isaac Stillman; seated (l to r):Sharon Maynard, S. Ananth Karumanchi, Franklin Epstein. (Photo by Steve Gilbert) The cause of preeclampsia has remained mysterious, and it has even been dubbed "the disease of theories" since competing models for its pathogenesis have been proposed but none proven. Now, researchers at HMS and Beth Israel Deaconess Medical Center have made a major advance by identifying a protein that may lead to the development of preeclampsia by blocking the activity of two angiogenic growth factors, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). The discovery sheds light on the etiology of the disease at the molecular level, points toward further research on its ultimate causes, and suggests potential early diagnosis and treatment strategies. "The rats 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." --S. Ananth Karumanchi "Currently, there is no treatment for this condition," also known as toxemia of pregnancy, said S. Ananth Karumanchi, HMS instructor in medicine at BID and senior author of the report in the March 3 Journal of Clinical Investigation. "The only management we can offer patients is to deliver the baby and the placenta." Preeclampsia typically develops after the 20th week of pregnancy and can rapidly progress to full-blown eclampsia with kidney failure, seizures, and other life-threatening complications. Co-author Franklin Epstein, the William Applebaum professor of medicine at HMS and BID, added that although typically thought of as an obstetric problem, "Preeclampsia is also the world's most common renal disease--and too little attention has been paid to this fact." A nephrologist, Karumanchi's interest in preeclampsia comes from the observation that the glomerulus--the kidney's filtration apparatus--is pathologically affected in this disease by glomerular capillary endotheliosis, in which endothelial cells become swollen and block the capillaries, which is believed to cause protein leakage into the urine. The Disease Trigger When a pregnancy proceeds normally, the network of blood vessels to the placenta is remodeled to supply increasing oxygen and nutrients to the fetus. But in preeclampsia, the placental blood supply is instead reduced. Scientists have long speculated that this placental ischemia leads the placenta to release something into the maternal circulation, triggering the harmful events in the mother's kidney, liver, blood, and nervous system. To identify this unknown factor, Karumanchi and colleagues took placental tissue from healthy and preeclamptic women and used microarray gene-expression profiling to see which genes were up- or down-regulated in preeclamptic patients. Finding many differences in gene expression, they focused on upregulated genes that encoded secreted proteins. One of these turned out to be soluble fms-like tyrosine kinase 1 (sFlt1), a VEGF receptor that blocks the growth factor's activity. VEGF is an important angiogenic factor both in health and disease. In cancer, excess VEGF helps tumors grow new blood vessels, and VEGF signaling inhibitors are in development as anticancer drugs. Karumanchi shared the microarray data with his co-author and mentor Vikas Sukhatme, the Aresty professor of medicine at HMS and chief of BID's Renal Division. Sukhatme knew that an anti-VEGF antibody being used in cancer therapy was causing hypertension and proteinuria in about 30 percent of patients. Checking with his oncology colleagues, he found that cancer patients treated with two unrelated VEGF inhibitors were developing similar symptoms. "That was the 'aha' moment," Sukhatme said. If three different drugs affecting VEGF signaling produced hypertension and proteinuria, sFlt1 might do the same if it crossed from the placenta into the maternal circulation. Further Evidence Seeking evidence that this is, in fact, what happens, first author Sharon Maynard, a renal fellow in Karumanchi's lab, in collaboration with the Department of Obstetrics and Gynecology at BID, found higher sFlt1 concentrations in the blood of preeclamptic vs. healthy pregnant women, which dropped within 48 hours of birth. And Jaime Merchan, an oncologist in Sukhatme's lab, showed that blood from preeclamptic women blocked vessel growth in an in vitro angiogenesis assay and that treatment with VEGF or PlGF reversed this inhibition. To test the idea in vivo, the researchers then injected sFlt1 into pregnant rats. "The resulting data was exciting," said Karumanchi. "The rats exposed to sFlt1 had distinct clinical and pathological symptoms of preeclampsia--including the characteristic endotheliosis--demonstrating for the first time a clear cause-and-effect relationship between this protein and this disease." It appears that sFlt1 "mops up" VEGF and PlGF, he said, and the loss of growth factors damages the mother's small blood vessels, leading to the diverse symptoms of preeclampsia and eclampsia. "This research will now evolve in several different directions," Karumanchi said. "First, we need to understand why sFlt1 is upregulated in preeclampsia." Genetic, immunological, and environmental factors will all need to be examined, he said, and maternalpaternal antigenic incompatibility may play a role. "Second, it will be interesting to see if measurement of blood sFlt1, VEGF, and PlGF levels will allow us to develop a test that can predict which patients will develop preeclampsia well before the onset of symptoms," he added. "Third, we have a rationale for using these growth factors, or other approaches that would block excess sFlt1, to see if they might be useful in treating the disease." One potential treatment is suggested by one of cigarette smoking's few benefits: a reduced incidence of preeclampsia that may be mediated by lowering sFlt1 and increasing VEGF production. This raises the possibility that short-term nicotine treatment might be used for severe preeclampsia. The work also has implications for anti-angiogenic cancer therapy, Sukhatme added. Although patients on VEGF-signaling inhibitors must be watched for hypertension and proteinuria, "there may be a silver lining," he said, since these symptoms could serve as surrogate markers for the drugs' efficacy. --Tom Reynolds