Placental HtrA3 Is Regulated by Oxygen Tension and Serum Levels Are Altered during Early Pregnancy in Women Destined to Develop Preeclampsia

Abstract

Context: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.Objective: The present study examined the placental production and the serum profile of HtrA3 across gestation in women, the potential molecular mechanisms regulating HtrA3 production, and the association between maternal HtrA3 serum levels and preeclampsia. Methods:Immunohistochemistry determined HtrA3 expression pattern and cellular localization in first-, second-, and third-trimester placenta. The maternal serum HtrA3 levels were analyzed by Western blotting. The regulation of placental HtrA3 production and the secretion by oxygen tension was investigated in first-trimester placental explants and trophoblast cells.Results: Placental HtrA3 protein was maximally produced in the first trimester and 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, whereas the transition from low to high oxygen decreased, HtrA3 protein production in syncytiotrophoblast. Maternal serum HtrA3 levels at approximately 13-14 wk of gestation were significantly higher in women who subsequently developed preeclampsia. It appeared that HtrA3 down-regulation was delayed in preeclamptic pregnancies. Conclusions:HtrA3 protein production is closely associated with changing in oxygen tension in the placenta. The decline in HtrA3 at the end of first trimester may reflect the placental low to high oxygen switch. Abnormally high levels of serum HtrA3 at approximately 13-14 wk of gestation is associated with preeclampsia. (J Clin Endocrinol Metab 96: 403-411, 2011) P reeclampsia is a serious disorder of human pregnancy affecting 5-10% of pregnant women (1). It contributes significantly to both maternal and fetal morbidity and mortality, accounting for about 18% of maternal and perinatal deaths in industrialized countries (2, 3). Preeclampsia is not diagnosed until it becomes clinically apparent late in pregnancy, at which time delivery is the only effective cure, often inflicting prematurity. The burden of preeclampsia thus also falls on the neonate because fetal survival rates inversely correlate with gestational age; survival rate for a baby born at 23 wk is less than 10% (4).

High-Temperature Requirement Protein A4 (HtrA4) Suppresses the Fusogenic Activity of Syncytin-1 and Promotes Trophoblast Invasion

“…Clinically, elevated expression of both HtrA1 and -3 is detected in preeclampsia (1,21). Moreover, HtrA3 expression is enhanced under hypoxic conditions (21). Here we show that HtrA4 expression is suppressed in BeWo cells by hypoxia, and so too is the invasiveness of BeWo cells.…”

“…HtrA2 is a mitochondrial serine protease that promotes apoptosis via interaction with and proteolysis of the IAP proteins, which contributes to caspase activation (13). Expression of both HtrA1 and -3 is detected at high levels in decidual cells and villous trophoblasts but is barely detectable in interstitial EVTs (21,31).…”

“…In the present study, we provide evidence that HtrA4 is a downstream effector of GCM1 stimulating placental cell invasion, most likely through proteolysis of ECM proteins. Clinically, elevated expression of both HtrA1 and -3 is detected in preeclampsia (1,21). Moreover, HtrA3 expression is enhanced under hypoxic conditions (21).…”

Placenta-derived exosomes: potential biomarkers of preeclampsia

“…60 It has been found to be associated with altered placental oxygen transfer and bloodvessel remodeling in the first trimester. 61 Elevated levels of HTRA3 in weeks 13-14 of gestation have been observed in PE-predisposed patients. 62 Although the potential application of HTRA3 as a biomarker is promising, it has limited application, since factors responsible for altered expression of this enzyme in PE are still unclear.…”

Maternal HtrA3 optimizes placental development to influence offspring birth weight and subsequent white fat gain in adulthood

“…To date, four mammalian HtrAs (HtrA1-4) have been identified [1][2][3][4][5][6][7] , and their dysregulation is associated with a number of diseases, including cancer, arthritis, neurodegenerative disorders, age-related macular degeneration, and pregnancy diseases [8][9][10][11][12][13][14][15][16][17] . In particular, HtrA1 and HtrA3 have been suggested as tumor suppressors, because they are down-regulated in a number of cancers and this reduction is suggested to promote tumorigenesis [18][19][20][21][22] .…”