Serine Peptidase HTRA3 Is Closely Associated with Human Placental Development and Is Elevated in Pregnancy Serum1

Abstract

HTRA3 is a newly identified serine peptidase of the mammalian HTRA (high-temperature requirement factor A) family, that is upregulated dramatically during mouse placental development. The current study determined whether HTRA3 was involved in human placentation. During the menstrual cycle, HTRA3 was expressed primarily in the endometrial glands, being significantly upregulated toward the mid- to late secretory phases; prominent expression in the stroma detected only in the decidual cells in the late secretory phase. Thus, overall endometrial HTRA3 expression was highest in the late secretory phase, when the endometrium is prepared for maternal-trophoblast interaction. During the first trimester of pregnancy, both glandular and decidual HTRA3 expression increased further with the decidual upregulation being highly significant. The strong link between HTRA3 expression and endometrial stromal cell decidualization was further established in an in vitro model using primary endometrial stromal cells. HTRA3 was also expressed by certain trophoblast subtypes in the first-trimester placenta: strongly in the villous syncytiotrophoblast, trophoblast shell, and endovascular trophoblast and weakly in the distal portion of the trophoblast cell columns but not in villous cytotrophoblast, the proximal region of the cell columns, or interstitial trophoblast. Upregulation of HTRA3 expression in association with placental development was revealed by a significant elevation of this protein in the maternal serum during the first trimester. We thus propose that HTRA3 is a previously unrecognized factor closely associated with and potentially important for human placentation. This study established crucial groundwork for future investigations toward establishing the physiological roles of HTRA3 in human placentation.

Distinct expression and localization of serine protease HtrA1 in human endometrium and first‐trimester placenta

“…However, the highest level of HtrA1 expression was found in the human placenta, suggesting that HtrA1 may play important roles in placental formation and function (Nie et al, 2003a). Our recent studies demonstrated that HtrA1 was, indeed, tightly regulated during placentation in the mouse (Nie et al, 2005), and that its closely related family member, HtrA3, is also strongly associated with placental development both in the mouse and human (Nie et al, 2003b(Nie et al, , 2006a.…”

“…Total RNA was isolated and Northern analysis (15 g/lane) performed as previously published (Nie et al, 2006a). RNA extracted from first-trimester placenta (n ϭ 4) and decidua (n ϭ 4) were examined individually.…”

Prediction of Preeclampsia – A Workshop Report

“…This dynamic expression of HtrA3 in the placenta throughout gestation was reflected by a similar change in its maternal serum concentrations. HtrA3 concentrations were higher in pregnant women than in non-pregnant women, and the highest concentrations were measured during the first trimester [10]. In the 13th-14th week of pregnancy, increased concentrations of HtrA3 were found in the sera of women who later developed preeclampsia compared to those who had a normal pregnancy.…”

“…The villous syncytiotrophoblast, the distal region of the trophoblast cell columns, and the endovascular extravillous trophoblasts strongly stained for HtrA3. While its decidual expression was maintained during gestation, placental expression of HtrA3 was down-regulated during the second and third trimesters, when it was only detectable in the syncytiotrophoblast [10]. This dynamic expression of HtrA3 in the placenta throughout gestation was reflected by a similar change in its maternal serum concentrations.…”

“…HtrA3 expression was increased in endometrial glands and stromal cells in the late secretory phase of the menstrual cycle, and a further increase in HtrA3 expression was observed in the first trimester of human pregnancy [10]. The villous syncytiotrophoblast, the distal region of the trophoblast cell columns, and the endovascular extravillous trophoblasts strongly stained for HtrA3.…”