t0901317 and Placenta-Diseases

Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which 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.. Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, 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)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice.. These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia.

Topics: Animals; Anticholesteremic Agents; Antigens, CD; Blood Pressure; Cell Line, Tumor; Choriocarcinoma; Endoglin; Female; Human Umbilical Vein Endothelial Cells; Humans; Hydrocarbons, Fluorinated; Hydroxycholesterols; Intracellular Signaling Peptides and Proteins; Ischemia; Liver X Receptors; Male; Matrix Metalloproteinase 14; Mice; Mice, Inbred C57BL; Mice, Transgenic; Orphan Nuclear Receptors; Placenta Diseases; Pre-Eclampsia; Pregnancy; Receptors, Cell Surface; Sulfonamides; Tissue Inhibitor of Metalloproteinase-3; Uterine Neoplasms