Abstract
The pathogenic origin of preeclampsia is defective placental development (placentation) and function. Preeclampsia is not diagnosed until later in pregnancy and reliable early detection is highly desirable. HtrA3 is a recently cloned gene with high expression during placentation in the mouse, rhesus monkey and human. In human 1st trimester placenta, HtrA3 is highly expressed in maternal decidual cells and in certain trophoblast cell types. Placental HtrA3 is secreted into the maternal circulation and clearly detectable in serum of pregnant women in the 1st trimester. The present study examined placental production and serum profile of HtrA3 across gestation in women, the potential molecular mechanisms regulating HtrA3 production, and association between maternal HtrA3 serum levels and preeclampsia. Immunohistochemistry determined HtrA3 expression pattern and cellular localization in 1st, 2nd and 3rd trimester placenta. Maternal serum HtrA3 levels were analysed by Western blotting. Regulation of placental HtrA3 production and secretion by oxygen tension was investigated in 1st trimester placental explants and trophoblast cells. Placental HtrA3 protein was maximally produced in the 1st trimester, then dramatically down-regulated, especially in the syncytiotrophoblast. HtrA3 was secreted into the maternal circulation with a serum profile reflecting placental production. Oxygen tension regulated HtrA3; low oxygen enhanced, while transition from low-to-high oxygen decreased, HtrA3 protein production in syncytiotrophoblast. Maternal serum HtrA3 levels at ~13-14 weeks of gestation were significantly higher in women who subsequently developed preeclampsia. It appeared that HtrA3 down-regulation was delayed in preeclamptic pregnancies. In conclusion, HtrA3 protein production is closely associated with oxygen tension in the placenta. The decline in HtrA3 at the end of 1st trimester may reflect the placental low-to-high oxygen switch. Abnormally high levels of serum HtrA3 at the end of 1st trimester is associated with preeclampsia.
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