Placental HtrA3 is regulated by oxygen tension and serum levels are altered during early pregnancy in women destined to develop preeclampsia.
BACKGROUND
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.
Prince Henry's Institute of Medical Research, Monash Medical Center, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Ying
Y
Li
Michelle
M
Puryer
Eliane
E
Lin
Kathryn
K
Hale
Lois A
LA
Salamonsen
Ursula
U
Manuelpillai
Stephen
S
Tong
Weng
W
Chan
Euan M
EM
Wallace
Guiying
G
Nie
D000328:Adult; D015415:Biomarkers; D002460:Cell Line; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D015726:Giant Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D009924:Organ Culture Techniques; D010101:Oxygen Consumption / Q000502:physiology*; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000097:blood / Q000175:diagnosis / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000378:metabolism; D011262:Pregnancy Trimester, Second / Q000378:metabolism; D011263:Pregnancy Trimester, Third / Q000378:metabolism; D012306:Risk; D012697:Serine Endopeptidases / Q000097:blood / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism
D015415:Biomarkers; C474013:HTRA3 protein, human; D012697:Serine Endopeptidases