Preeclampsia is the leading cause of maternal death and is associated with a fivefold increase in perinatal infant mortality in the United States. Although the signs of preeclampsia (altered maternal vascular function, fetal growth retardation) are well known, its causes remain obscure. Compelling evidence implicates the placenta in the etiology. In preeclampsia, as compared with normal pregnancy, placentation is shallow. As a result, the supply of maternal blood to the placenta is reduced. Work during the first grant period showed that the anatomic findings reflect an abnormality in the cytotrophoblast (CTB) differentiation pathway that results in invasion. Work during the second grant period showed that normal CTBs cultured in an hypoxic environment replicate the abnormal differentiation/invasion that occurs in preeclampsia and dramatically increase their release of substances that alter vascular function, including tumor necrosis factor-alpha and endothelin-1. These results suggest that a reduction in O2 tension at the maternal-fetal interfact is key to the CTB defects and the maternal signs associated with preeclampsia. This application now proposes a systematic approach for identifying molecules produced by the inadequately perfused placenta that could play a role in the disease process. The experimental strategy reflects on fact that alterations in maternal vascular function are an important sign of preeclampsia. Thus, Aim 1 focuses on how hypoxia changes the repertoire of substances cultured placental cells secrete that alter vascular function. In accord with previous work, it is expected that placental cells isolated from preeclamptic patients will show some of these same alterations. The experimental strategy also reflects that fact that little is known about the etiology of this complex syndrome, whose causes could be removed by many steps from the endpoints that are observed and could involve molecules other than well characterized vasoactive substances. Thus, Aim 2 focuses on clarifying, at a fundamental level, how hypoxia and preeclampsia affect the placental protein repertoire. Two-dimensional polyacrylamide gel electrophoresis will be followed by a combination of immunological detection and protein sequencing techniques to identify proteins whose expression changes. Molecules thus identified will be assayed for their effects on vascular function and CTB invasion/differentiation, both of which are abnormal in preeclampsia. Finally, Aim 3 focuses on determining how placental factors whose in vitro expression is altered by hypoxia and/or preeclampsia are related to the disease process in vivo. It is predicted that levels of relevant molecules will change both in the placenta and in maternal blood. Together, these experiments will show whether hypoxia and preeclampsia have similar effects on the repertoire of factors, including vasoactive substances, that placental cells produce. In addition, they will identify molecules that could link the inadequately perfused placental to the maternal vascular disease, an important first step toward designing tests to predict women at risk for developing preeclampsia and devising rational therapies for treating the signs.
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