Thromboxane A(2) limits differentiation and enhances apoptosis of culturedhuman trophoblasts

Prostanoids influence differentiation in diverse cell types. Altered expres sion of cyclooxygenase and prostaglandins has been implicated in the pathop hysiology of placental dysfunction, which results in preeclampsia and fetal growth restriction. We hypothesized that prostanoids modulate differentiat ion 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 biochemic al 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 morphologi c differentiation of cultured trophoblasts. As expected, human chorionic go nadotropin levels in the media were elevated in a concentration-dependent m anner in the presence of the thromboxane synthase inhibitor, sodium furegre late, or the thromboxane A(2) receptor blocker SQ 29,548. Furthermore, thro mboxane A(2) enhanced trophoblast apoptosis, determined using terminal deox ynucleotidyl transferase-mediated dUTP nick-end labeling staining, cell mor phology, and a concentration-dependent increase in p53 expression. We concl ude that thromboxane A(2) hinders differentiation and enhances apoptosis in cultured trophoblasts from term human placenta. We speculate that thrombox ane may contribute to placental dysfunction by restricting differentiation and enhancing apoptosis in human trophoblasts.