Placental plasminogen activator inhibitor 1 is induced by platelet-derived TGF-β independently of TGF-β receptor 3 and is upregulated in preeclampsia

Abstract Preeclampsia is a pregnancy complication associated with de novo gestational hypertension, proteinuria, and dysregulations in the coagulation and fibrinolytic systems. Platelet-derived factors include various growth and differentiation factors, such as transforming growth factor (TGF)-β. The TGF-β type III receptor (TGFBR3), also known as betaglycan, is a co-receptor for the TGF-β superfamily and an important regulator of reproduction and fetal development. Here, we test the hypothesis whether or not TGFBR3 is involved in platelet-mediated upregulation of placental plasminogen activator inhibitor-1 (PAI-1). Perivillous fibrin deposits and PAI-1 levels were analyzed via immunohistochemistry, gene expression as well as protein expression in healthy and preeclamptic placental tissue. Placental villi and trophoblast cell line BeWo were incubated in presence or absence of washed platelets from pregnant women, platelet-derived soluble factors, or platelet-derived extracellular vesicles. Additionally, BeWo cells were treated with TGF-β-receptor inhibitors and silenced for TGFBR3 expression. PAI-1 and its encoding gene SERPINE1, as well as perivillous fibrin deposits, were significantly increased towards term of gestation and showed a significant upregulation in placental villi from preeclamptic pregnancies. Furthermore, SERPINE1 and PAI-1 were substantially upregulated in response to washed platelets and platelet-derived factors, but not to platelet-derived extracellular vesicles. The upregulation of SERPINE1 was blocked to control levels with the TGF-β inhibitor P144, whereas silencing of TGFBR3 had no effect. Our results suggest that platelet-derived factors induce placental PAI-1 expression independently of TGF-β receptor 3. Increased maternal platelet activation may contribute to significantly upregulated placental PAI-1 and perivillous fibrin deposits in preeclampsia.