Thromboxane A(2) limits differentiation and enhances apoptosis of cultured human trophoblasts.
Prostanoids influence differentiation in diverse cell types. Altered expression of cyclooxygenase and prostaglandins has been implicated in the pathophysiology of placental dysfunction, which results in preeclampsia and fetal growth restriction. We hypothesized that prostanoids modulate differentiation and apoptosis in cultured human trophoblasts. Villous cytotrophoblasts were isolated from term human placentas and cultured in serum-free medium. The level of human chorionic gonadotropin was used as a marker of biochemical differentiation of primary trophoblasts, and syncytia formation was used as a marker of morphologic differentiation. Of the prostanoids tested, we found exposure to thromboxane A(2) hindered both biochemical and morphologic differentiation of cultured trophoblasts. As expected, human chorionic gonadotropin levels in the media were elevated in a concentration-dependent manner in the presence of the thromboxane synthase inhibitor, sodium furegrelate, or the thromboxane A(2) receptor blocker SQ 29,548. Furthermore, thromboxane A(2) enhanced trophoblast apoptosis, determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, cell morphology, and a concentration-dependent increase in p53 expression. We conclude that thromboxane A(2) hinders differentiation and enhances apoptosis in cultured trophoblasts from term human placenta. We speculate that thromboxane may contribute to placental dysfunction by restricting differentiation and enhancing apoptosis in human trophoblasts.
Yusuf
K
K
Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis, Missouri 63110-1094, U.S.A.
Smith
S D
SD
Levy
R
R
Schaiff
W T
WT
Wyatt
S M
SM
Sadovsky
Y
Y
Nelson
D M
DM
D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology; D006801:Humans; D011225:Pre-Eclampsia / Q000209:etiology; D011247:Pregnancy; D013928:Thromboxane A2 / Q000494:pharmacology*; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D006063:Chorionic Gonadotropin; D016159:Tumor Suppressor Protein p53; D013928:Thromboxane A2