Preeclampsia is a multisystem disorder unique to human pregnancy. It is a leading cause of fetal growth retardation, infant morbidity and mortality associated with premature delivery, and maternal death. Several abnormalities, including vascular endothelial cell dysfunction, have been implicated in the pathogenesis of preeclampsia. However, the mechanisms that underlie the endothelial cell function are poorly understood. The studies outlined in this proposal relate the abnormal placental trophoblast function of preeclampsia with neutrophil activation and endothelial cell dysfunction. We also address potential cellular and molecular mechanisms that contribute to the altered endothelial cell function in preeclampsia. Our central hypothesis is that placental trophoblasts experience an oxidative stress that results in the disturbance of neutrophil and endothelial cell function. This process, coupled to alteration of neutrophil-endothelial interactions, leads to the endothelial cell dysfunction. This hypothesis will be tested by experiments outlined under 3 specific aims: 1) To characterize the placental trophoblast dysfunction in preeclampsia; 2) To elucidate the mechanisms of placental factor-mediated activation of neutrophils; 3) To elucidate the cellular and molecular mechanisms of placental factor-mediated endothelial cell dysfunction. In this study, trophoblasts and endothelial cells from both normal and preeclamptic pregnancies will be isolated and used as testing models. Experiments are proposed to assess trophoblast abnormalities in preeclampsia, to character placental factor(s) in mediating neutrophil activation, to examine trophoblast-endothelial cell interactions using co-cultures of the two cell types, and to address the role of placental factor(s) in regulating endothelial cell transcription factor and mRNA expression. We believe that the information obtained from this proposed project will extend our knowledge of the pathogenesis of preeclampsia and provide potential avenues for therapeutic intervention in women suffering from this disorder.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036822-02
Application #
6164935
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
1999-03-17
Project End
2004-02-29
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
2
Fiscal Year
2000
Total Cost
$137,077
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Ma, Rong; Gu, Baihan; Gu, Yang et al. (2014) Down-regulation of TIMP3 leads to increase in TACE expression and TNF? production by placental trophoblast cells. Am J Reprod Immunol 71:427-33
Gu, Yang; Sun, Jingxia; Groome, Lynn J et al. (2013) Differential miRNA expression profiles between the first and third trimester human placentas. Am J Physiol Endocrinol Metab 304:E836-43
Wang, Yuping; Alexander, J Steven (2013) Role of chymase in preeclampsia. Curr Vasc Pharmacol 11:606-15
Wang, Yuping; Fan, Ruping; Gu, Yang et al. (2012) Digoxin immune fab protects endothelial cells from ouabain-induced barrier injury. Am J Reprod Immunol 67:66-72
Gu, Y; Groome, L J; Alexander, J S et al. (2012) PAR-2 triggers placenta-derived protease-induced altered VE-cadherin reorganization at endothelial junctions in preeclampsia. Placenta 33:803-9
Ma, Rong; Gu, Yang; Zhao, Shuang et al. (2012) Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies. Am J Physiol Endocrinol Metab 303:E928-35
Alexander, Jonathan Steven; Wang, Yuping (2012) Therapeutic potential of Schisandra chinensis extracts for treatment of hypertension. Introduction to: 'antihypertensive effect of gomisin A from Schisandra chinensis on angiotensin II-induced hypertension via preservation of nitric oxide bioavailability' Hypertens Res 35:892-3
Wang, Yuping; Lewis, David F; Gu, Yang et al. (2011) Elevated maternal soluble Gp130 and IL-6 levels and reduced Gp130 and SOCS-3 expressions in women complicated with preeclampsia. Hypertension 57:336-42
Wang, Yuping; Alexander, J Steven (2011) Analysis of endothelial barrier function in vitro. Methods Mol Biol 763:253-64
Ma, R; Gu, Y; Groome, L J et al. (2011) ADAM17 regulates TNF? production by placental trophoblasts. Placenta 32:975-80

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