Activin A and activin receptors in gestational tissue from preeclamptic pregnancies

Abstract

Maternal serum activin A levels are elevated in women with preeclampsia. To explore whether this could be due, at least in part, to increased production by the gestational tissues, we have measured activin A in the serum of women with (n=23) or without preeclampsia (n=62) at 29-40 weeks of gestation and in placenta and fetal membranes from preterm preeclamptic (PT-PE, n=8), term preeclamptic (T-PE, n=10) and healthy term controls (T-C, n=10). We have also explored if there are associated changes in activin receptor Alk2, ActRII and ActRIIB in these tissues. The relative amounts of receptor proteins were measured by densitometry on Western blots and receptors and activin A subunit localised by immunohistochemistry in PT-PE, T-PE and T-C gestational tissues (n=8-10/group).Maternal serum activin A levels were significantly elevated in women with preeclampsia (multiples of the normal median (MoM)=3·5, P<0·0001, Mann-Whitney U test) compared with healthy women (median MoM=1·0). Compared with control tissues, the activin A content was significantly higher in preeclamptic placentae (P=0·001 and P=0·0005 for PT-PE and T-PE respectively, Mann-Whitney U test), but significantly lower in the amnion (P=0·005 and P=0·014 for PT-PE and T-PE respectively) and choriodecidua (P=0·009 for T-PE). The maternal serum activin A level in women with preeclampsia was significantly correlated with elevated placental production (P=0·01, Pearson's correlation). Receptor Alk2 protein levels were significantly elevated in T-PE placentae (P=0·0006, Mann-Whitney U test), ActRIIB levels were significantly lower in PT-PE placentae (P=0·01) and ActRII levels were significantly lower in PT-PE choriodecidua (P=0·0002) compared with controls. There were no apparent differences in the distribution of the A subunit and receptors Alk2, ActRII and ActRIIB between control and preeclamptic tissues.These findings suggest that elevated levels of activin A in the maternal circulation in association with preeclampsia are due, at least in part, to increased placental production, and that the regulation of activin synthesis in placenta and fetal membranes is differentially regulated. Further, the differences in activin receptor protein levels between preeclamptic and control placenta and choriodecidua suggest that activin A-induced regulation may be altered in preeclampsia.

Pregnancy-associated and placental proteins in the placental tissue of normal pregnant women and patients with pre-eclampsia at term

“…However, immunostaining with inhibin a subunit and or bA subunit does not confirm the presence of the biologically active dimeric inhibin A and/or activin A in the placenta. Recently, placental extracts from pre-eclampsia patients have been shown to have increased levels of activin A at term and pre-term compared with normal term controls (32). Whilst, in our Table 2).…”

“…We have set out to investigate if there is any difference in the placental content of trophoblast-specific and associated markers in pre-eclampsia compared with normal pregnancies. Activin A was recently reported to be increased in placental (but not in other gestational) tissue of preeclampsia patients (32). Our first group included SP1 and human placental lactogen (HPL, originating specifically from the placenta), and the second group contains markers that are produced mostly but not exclusively by the placenta in pregnancy (PAPP-A, inhibin A, activin A, follistatin, PLGF, leptin).…”

Activin A Plasma Levels at Birth: An Index of Fetal Hypoxia in Preterm Newborn

“…With respect to the source of this rise of activin A in cord blood of hypoxic neonates, increased expression of activin subunit proteins (30) has been described in placentas of preg- 698 nant women with preeclampsia or fetal growth restriction, suggesting that increased levels of activin A in hypoxic newborns may partially be due to increased placental expression and synthesis. However, recent in vitro data revealed that hypoxia significantly reduced synthesis and secretion of activin A by the human placenta (31,32).…”

Oxidative stress increases placental and endothelial cell activin A secretion

“…In pregnancies complicated by placental dysfunction as evidenced by intrauterine foetal growth restriction (Bobrow et al 2002, Barkehall-Thomas et al 2006 or preeclampsia (Muttukrishna et al 1997, D'Antona et al 2000, Manuelpillai et al 2001, Silver et al 2002, maternal serum levels of activin A are significantly higher than observed in normal pregnancy. While these increased circulating levels of activin A are thought to arise from increased placental production (Manuelpillai et al 2001, Silver et al 2002) the mechanism(s) underlying such increased placental output remain unclear.…”