Oxysterol-Induced Soluble Endoglin Release and Its Involvement in Hypertension
Background—Ischemia in the placenta is considered as the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome where soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng.
Methods and Results—Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase of sEng parallel to an elevated formation of reactive oxygen species (ROS). Because ROS are related with the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol (22-R), a natural ligand of the liver X receptor (LXR) and the LXR synthetic agonist, T0901317. Treatment of JAR cells or human placental explants with 22-R or T0901317 resulted in a clear increase of sEng that was dependent on LXR. These LXR agonists induced an increased MMP-14 expression and activity as well as a significant reduction of its endogenous inhibitor TIMP-3. Also, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in blood pressure (AP). Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus MMP-14 cleavage site G-L prevented the oxysterol-dependent increase of AP and sEng levels in mice.
Conclusions—These studies provide a clue to understand the involvement of the LXR pathway in the sEng release and its contribution to pathogenic role in vascular disorders such as preeclampsia.
- Received February 22, 2012.
- Accepted October 19, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited