Preeclampsia occurs in 7-10% of pregnancies causing extensive fetal and maternal mortality and morbidity. Its etiology is obscure, and therapy empiric. In this proposal we will examine the abnormal trophoblastic invasion of decidual vessels and its linkage to systemic manifestations of the disorder and test the hypothesis that trophoblast histocompatibility antigens are differently expressed and regulated in preeclampsia. Predictive tests will also be established and validated. We plan to characterize the determinants of the normal interaction of early human trophoblast with extracellular matrix in vitro and examine the expression and regulation of HLA antigens in trophoblast. To determine whether these changes are primary, similar studies performed on first trimester chorionic villus samples will be matched with pregnancy outcome. Animal and human studies will test the hypothesis that endothelial injury causes many of the pathophysiological changes of preeclampsia. Evidence for endothelial cell injury in vivo will be determined by examination of maternal and umbilical vessels and by quantitating endothelial fibronectin and mitogenic activity in the blood of preeclamptic women. In preliminary studies, sera from preeclamptic women, prior to but not after delivery, caused cytolysis of endothelial cells in vitro. We will extend these studies and determine their relevance to the pathophysiology of the disorder by examining endothelial cell functions including procoagulant activity, prostacyclin production and vasodepressor activity, and expression of platelet derived growth factor after exposure to preeclamptic and control serum. The factor(s) in serum leading to these changes will be characterized and their source determined. Our hypothesis, that the origin is from trophoblast and is responsible for the multisystemic changes of preeclampsia, will be specifically tested. Sera from preeclamptic women and matched controls, obtained and stored from early pregnancy, will be analyzed for the serum factor and fibronectin to test that these changes precede clinically evident preeclampsia; and correlated with responses of skin blood flow to non-invasive vasoconstrictor and dilatory stimuli to establish predictive tests for preeclampsia. An animal model of preeclampsia, pregnant rhesus monkeys made hypertensive and proteinuric by partial aortic occlusion, will be used to determine whether endothelial injury is the result of reduced vascular perfusion or a primary pathogenetic factor. Serum from these animals will be assayed for fibronectin, mitogenic and endothelial cell cytolytic activity before and at intervals after aortic narrowing and correlated with hemodynamic changes. Examination of the monkey's decidua and placentas will determine if differences found in these tissues are the cause or result of reduced trophoblast perfusion. Likewise HLA antigen shedding, proposed as a causal factor in the altered HLA expression, will be examined in this model to test its possible primary role. With these studies we hope to identify preeclamptic patients at an early stage, better understand the etiology of the disorder and provide insights which aid rational therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD024180-04
Application #
3097133
Study Section
Maternal and Child Health Research Committee (HDMC)
Project Start
1988-05-01
Project End
1993-04-30
Budget Start
1991-05-01
Budget End
1992-04-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wilson, Lawriston; Ching, Yung-Hao; Farias, Michael et al. (2005) Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations. Genome Res 15:1095-105
Taylor, R N; de Groot, C J M (2004) Pre-eclampsia and vascular activation in women and non-human primates. Gynecol Obstet Invest 57:38-40
Schimenti, J C; Libby, B J; Bergstrom, R A et al. (2000) Interdigitated deletion complexes on mouse chromosome 5 induced by irradiation of embryonic stem cells. Genome Res 10:1043-50
de Groot, C J; Murai, J T; Vigne, J L et al. (1998) Eicosanoid secretion by human endothelial cells exposed to normal pregnancy and preeclampsia plasma in vitro. Prostaglandins Leukot Essent Fatty Acids 58:91-7
Vigne, J L; Murai, J T; Arbogast, B W et al. (1997) Elevated nonesterified fatty acid concentrations in severe preeclampsia shift the isoelectric characteristics of plasma albumin. J Clin Endocrinol Metab 82:3786-92
de Groot, C J; Davidge, S T; Friedman, S A et al. (1995) Plasma from preeclamptic women increases human endothelial cell prostacyclin production without changes in cellular enzyme activity or mass. Am J Obstet Gynecol 172:976-85
de Groot, C J; Chao, V A; Roberts, J M et al. (1995) Human endothelial cell morphology and autacoid expression. Am J Physiol 268:H1613-20
Chiang, M H; Steuerwald, N; Lambert, H et al. (1994) Detection of human leukocyte antigen class I messenger ribonucleic acid transcripts in human spermatozoa via reverse transcription-polymerase chain reaction. Fertil Steril 61:276-80
Friedman, S A; de Groot, C J; Taylor, R N et al. (1994) Plasma cellular fibronectin as a measure of endothelial involvement in preeclampsia and intrauterine growth retardation. Am J Obstet Gynecol 170:838-41
Combs, C A; Rosenn, B; Kitzmiller, J L et al. (1993) Early-pregnancy proteinuria in diabetes related to preeclampsia. Obstet Gynecol 82:802-7

Showing the most recent 10 out of 27 publications