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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Ilekis, John V
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Louisiana State University Hsc Shreveport
Obstetrics & Gynecology
Schools of Medicine
United States
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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
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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
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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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