Symposium 2-3 - Thrombomodulin as a new therapeutic target for preeclampsia

Abstract

Thrombomodulin (TM) is a transmembrane glycoprotein abundantly expressed on vascular endothelial cells and have been known as molecules with anticoagulant and anti-inflammatory properties. TM binds to a danger signal, HMGB1, and suppresses the inflammatory response induced by HMGB1. This study aimed to clarify the relationship between HMGB1 and the pathological mechanisms of preeclampsia (PE). Additionally, we explored the therapeutic potential of TM for PE. We used angiotensin II (AngII)-induced PE mouse model, in which continuous administration of Ang II using subcutaneous pump developed PE symptoms in pregnant mice. AngII administration caused placental release of HMGB1, leading to enhanced production of sFlt-1 and the inflammatory cytokines in trophoblast cells. When TM was given to the PE mouse model, improvements in fetal growth, maternal hypertension and urinary protein were observed. Furthermore, in-vitro experiments suggest that antagonism of HMGB1 underlies the therapeutic effect of TM on PE. In the studies using the serum samples and placental tissues obtained from pregnant women, HMGB1 and TM levels in peripheral blood were higher in pregnant women with PE, and there was a negative correlation between the two in pregnant women with PE. Immunostaining of PE placentas showed HMGB1 release from the nucleus and defective staining of membrane-type TM on the surface of syncytiotrophoblast. These findings supported that the increased HMGB1 and TM levels in the peripheral blood of PE women originated from the placenta. In conclusion, HMGB1 released from the dysfunctional placenta is deeply involved in the pathogenesis of PE and that inhibition of HMGB1 action by TM leads to improvement of placental function. Treatment strategy aiming to inhibit HMGB1 action, including TM, is a new therapeutic approach for PE.