Thrombomodulin promotes placental function by up-regulating placental growth factor via inhibition of high-mobility-group box 1 and hypoxia-inducible factor 1α

Introduction: Pregnancy is a state of maternal systemic stress due to inflammation and hypoxic reactions originating from the utero-placental unit. Maternal tolerance to these stresses is a key for successful outcomes. Thrombomodulin (TM), a glycoprotein expressed on cell surface, regulates local inflammatory pathways by inhibiting proinflammatory factor, High-mobility-group box1(HMGB1). Although TM is highly expressed on placental trophoblast cells, biological activities of TM during pregnancy remains unclear. Here, we hypothesized that TM may contribute to the maternal stress coping mechanisms. Methods: By administering recombinant-TM (rTM) to the pregnant mice, we investigated the influence of TM functions on the placenta and fetal growth. We further examined its effect on trophoblast cells, focusing on HMGB1-regulated inflammatory signalings and hypoxia-inducible factor 1 alpha (HIF1 alpha)-dependent regulation of placental angiogenic factors. Results: Administration of rTM increased fetal weight and fetal/placental-weight ratios, which implies the improvement of placental function. These features were accompanied by maternal serum HMGB1 reduction and suppressed placental proinflammatory cytokine, IL-6 and TNF-alpha, expressions. In addition, rTM reduced HIF1 alpha protein accumulation and enhanced placental growth factor (PlGF) expression in the placenta, that explains the improvement of maternal features. Discussion: Our study revealed the supportive effect of TM on the placental function in mice. By inhibiting HMGB1, rTM suppresses proinflammatory cytokines, downregulates HIF1 alpha and induces PlFG expression in the placental tissue. Our results have elucidated the novel aspects of TM; the regulation of placental inflammatory cytokines and angiogenic factors, during pregnancy. These findings may reveal potential therapeutic opportunities for the management of maternal complications.