Exaggerated inflammatory response and increased oxidative stress are the two major pathophysiological manifestations of the altered endothelial function in women with preeclampsia (PE), a multi-system disorder unique to human pregnancy. Although the etiology of PE is not known, it is believed that 'toxic'factors derived from placental trophoblasts (TCs) enter the maternal circulation and induce EC dysfunction. In the initial funding period of this project, we identified that chymotrypsin-like protease (chymase) derived from placental TCs is responsible for upregulation of EC P-selectin and E-selectin expression, key molecules of increased EC inflammatory response in PE. In this renewal grant application, we will further investigate the role of placental chymase and the potential cellular and molecular mechanisms of this protease in regulation of EC function that account for the altered EC function associated with PE. Our central hypothesis is that chymase produced by placental TCs not only initiates an inflammatory phenotype in ECs but also induces EC oxidative stress and vasoactivator release that characterize the EC dysfunction in PE. This hypothesis directly links placental trophoblast aberration and EC dysfunction, which will be tested by experiments outlined under 4 specific aims: 1) to characterize the chymase (chymotrypsin-like protease) in placentas from normal and PE pregnancies, 2) to determine if placental chymase is responsible for activating ECs and inducing an inflammatory phenotype in PE, 3) to address whether placenta-derived chymase induces endothelial oxidative stress in PE, and 4) to explore if chymase-induced EC vasoconstrictor release that stimulates vasoconstriction in PE. The proposed work will employ uterine myometric vascular ECs (UtMVECs), umbilical cord ECs, TCs, and VSMCs. ECs cultured with TC or TC conditioned medium will be used to study mechanisms underlying the placental chymase-induced alterations in EC function during PE. Co-culture of ECs with VSMCs will be employed to study effects of ECs and circulating factors on VSMC contractility that mimic a vascular response of relevance to PE. The proteins, genes and signal transduction pathways involved in chymase-induced EC dysfunction will also be studied. Results obtained from the proposed work should enhance our knowledge and establish a direct link of placental TC activity and EC dysfunction in PE.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036822-09
Application #
7603116
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
1999-03-17
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2009
Total Cost
$185,926
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
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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
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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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