Building on their earlier discovery which found that elevated levels of the sFlt1 placental protein leads to the onset of preeclampsia, researchers at Beth Israel Deaconess Medical Center (BIDMC), in collaboration with a research team from The Hospital for Sick Children, Toronto, have identified a second protein which, in combination with sFlt1, escalates preeclampsia to a severe - and life-threatening - state.
These new findings, reported in Nature Medicine, provide another critical piece of information about this puzzling disease, which complicates five percent of all pregnancies worldwide and is a major cause of maternal and fetal mortality, particularly in developing nations.
"Preeclampsia typically develops in the third trimester of pregnancy and is characterized by high blood pressure, edema and protein in the urine," explains the study's senior author S. Ananth Karumanchi, MD, a nephrologist in the Center for Vascular Biology at BIDMC and Assistant Professor of Medicine, Obstetrics and Gynecology at Harvard Medical School.
Three years ago, Karumanchi and his colleagues demonstrated that the placenta plays a central role in the course of these events, and that elevated levels of a placental protein called sFlt1 (soluble fms-like tyrosine kinase) are key to the onset of the disease.
However, for unknown reasons, a subset of preeclampsia patients will go on to experience severe preeclampsia - a group of dramatically escalated symptoms characterized by a sudden, massive rise in blood pressure, which can lead to the onset of seizures, as well as the development of fetal growth restriction and the HELLP syndrome. HELLP, which stands for hemolysis, elevated liver enzymes and low platelets, indicates that the mother's liver and blood-clotting systems are not functioning properly, and the health of both mother and infant are in serious danger.
"During the course of our previous experiments [to confirm the role of sFlt1 in the disease] we observed that although all of the animals treated with sFlt1 exhibited telltale symptoms of hypertension and proteinuria, they did not all go on to develop symptoms of the HELLP syndrome," notes Karumanchi.
"We, therefore, hypothesized that other placenta-derived proteins must be acting jointly with sFlt1 to induce vascular damage and escalate the disease to its severe form."
Using microarray analysis of human placental specimens from patients with preeclampsia, Karumanchi and his coauthors observed that a protein known as endoglin was significantly upregulated. (Endoglin was discovered 20 years ago in the laboratory of study collaborator Michelle Letarte at The Hospital for Sick Children, Toronto.) A co-receptor for transforming growth factor beta family proteins, endoglin is expressed on endothelial cells lining the blood vessels, and thereby plays an important role in maintaining the health and integrity of the vascular system.
"Our further investigations revealed that the extracellular region of the endoglin protein is shed into maternal circulation," explains Karumanchi. "We discovered that this shed form -- referred to as 'soluble endoglin' - was circulating in very high quantities among women with severe forms of preeclampsia."
In order to understand the protein's biological role, the investigators next administered soluble endoglin to pregnant rats; their results showed that this protein was indeed amplifying the vascular damage mediated by sFlt1, resulting in the symptoms of severe preeclampsia.
"What is apparently happening is that both sFlt1 and soluble endoglin are inhibiting the functions of two angiogenic growth factors - vascular endothelial growth factor [VEGF] and transforming growth factor beta," explains Karumanchi. "The diminished signaling of these growth factors in the vasculature adversely affects the health of the mother's small blood vessels." The result is the onset of severe preeclampsia and its dangerous consequences for both mother and infant.
"We believe that these latest findings will have important diagnostic and therapeutic implications for the management of this disease," says Karumanchi.
Adds Benjamin Sachs, MBBS, DPH, Chief of the Department of Obstetrics and Gynecology at BIDMC, "Preeclampsia affects 200,000 pregnancies a year in the United States and often leads to premature births. Severe preeclampsia is one of the world's leading causes of maternal and fetal mortality and poses a particular risk to women in developing countries. This new information provides us with another key piece of evidence as we work toward developing the means to diagnose, and eventually treat, this disease."
Study coauthors include BIDMC investigators Shivalingappa Venkatesha, PhD, Chun Lam, MD, Jun-ichi Hanai, MD, PhD, Tadanori Mammoto, MD, PhD, Yuval Bdolah, MD, Kee-Hak Lim, MD, Hai-Tao Yuan, MD, Towia Libermann, PhD, Isaac Stillman, MD, Franklin Epstein, MD, Frank Sellke, MD, PhD, and Vikas Sukhatme, MD, PhD; Mourad Toporsian, PhD, and Michelle Letarte, PhD, of The Hospital for Sick Children, University of Toronto, Ontario, Canada; Yeon Kim, MD, and Roberto Romero, MD, of the National Institute of Child Health and Human Development, Bethesda, Maryland; Drucilla Roberts, MD, PhD, of Massachusetts General Hospital; and Patricia D'Amore, PhD, of Schepens Eye Research Institute, Boston.
This study was funded, in part, by grants from the National Institutes of Health and the Heart and Stroke Foundation of Ontario.
BIDMC has filed patents on methods of diagnosing and treating preeclampsia.