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Placental Trophoblast-Derived Factors Diminish Endothelial Barrier Function

Departments of Obstetrics and Gynecology (Y.W., D.F.L., Y.G., Y.Z.), and Molecular and Cellular Physiology (J.S.A., D.N.G.), Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130

Address all correspondence and requests for reprints to: Yuping Wang, M.D., Ph.D., Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, P.O. Box 33932, Shreveport, Louisiana 71130. E-mail: ywang1{at}lsuhsc.edu.

Although increased vascular permeability is an important event in the pathogenesis of preeclampsia, the origin of the circulating factor(s) that elicits this endothelial barrier dysfunction is not known. In this study, we use coculture of endothelial cells and placental trophoblast cells to determine whether placental trophoblasts are a potential source of the factor(s) that mediate the increased vascular permeability of preeclampsia. Human umbilical vein endothelial cells grown in Transwell inserts or on coverslips were cocultured with trophoblast cells isolated from normal and preeclamptic placentas or placenta conditioned media. Endothelial cell barrier function was determined by: 1) measurements of electrical resistance and leakage of horseradish peroxidase, and 2) immunofluorescent staining of vascular endothelial-cadherin, pan-cadherin, and occludin. Uterine myometrium endothelial cells were also studied for comparison. We observed the following: 1) electrical resistance was significantly (P < 0.01) decreased (compared with control endothelial cells) in endothelial cell monolayers cocultured with normal trophoblast cells and further reduced in endothelial cells cocultured with preeclamptic trophoblast cells; 2) an increased horseradish peroxidase leakage that was correlated with the decreased electrical resistance in cocultured cells; and 3) disorganized tight junction proteins and an altered distribution of vascular endothelial-cadherin and occludin in monolayers of endothelial cells cocultured with preeclamptic trophoblast cells. Similar responses were noted in uterine myometrium endothelial cells. We conclude that: 1) placental trophoblast cells produce factors that diminish the barrier function of endothelial cells; 2) endothelial tight junctions are more susceptible to factors released from preeclamptic trophoblast cells than from normal trophoblast cells; and 3) these results implicate trophoblast-derived factors in the increased vascular permeability associated with preeclampsia.

This work was supported in part by Grant HD36822 from the National Institutes of Health, National Institute of Child Health Development, and by Grants HL 67997 and HL26441 from the National Heart, Lung, and Blood Institute.

Results of this study were presented at the 50th Annual Meeting of the Society for Gynecologic Investigation, Washington, D.C., March 27–31, 2003.

Abbreviations: HRP, Horseradish peroxidase; HUVEC, human umbilical vein endothelial cell; MMP, matrix metalloproteinase; UtMEC, uterine myometrium endothelial cell; VE, vascular endothelial.

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