It has been well documented that pre-eclampsia and unexplained fetal growth restriction (FGR) have a common etiological background, but little is known about their linkage at the molecular level. The aim of this study was to further investigate the mechanisms underlying pre-eclampsia and unexplained FGR.

Pregnancy-associated plasma protein-A and -A2 (PAPP-A and -A2) are proteases that cleave insulin-like growth factor-binding proteins (IGFBPs), resulting in local activation of IGF signaling pathways. Here, we examined PAPP-A and -A2 mRNA and protein levels in placenta and maternal sera from women with pre-eclampsia and compared them with samples from uncomplicated pregnancy. PAPP-A2 but not PAPP-A mRNA and protein were elevated in pre-eclamptic placenta (P < 0.01). PAPP-A2 is normally produced in placental syncytiotrophoblast cells and maternal decidua. PAPP-A2 in syncytiotrophoblast cells was dramatically increased in pre-eclampsia. Maternal serum concentrations of PAPP-A2 but not PAPP-A were also significantly elevated in pre-eclampsia as compared with uncomplicated pregnancy. mRNA levels of IGFBP5, a specific substrate for PAPP-A2 protease activity, were also significantly increased, suggesting a potential role for IGFBP5 in fetal and placental growth suppression during pre-eclampsia. However, IGFBP5 protein levels were not increased in placenta from pre-eclampsia, possibly due to cleavage by up-regulated PAPP-A2. These data might imply that PAPP-A2 may be up-regulated in pre-eclamptic pregnancy to compensate for IGFBP5-mediated suppression of the IGF pathway, although final birthweights are still low in pre-eclamptic pregnancy.

Objective: It is well documented that anti-angiogenic factors are likely to play essential roles in the etiology of pre-eclampsia. Apelin is a small peptide that may potentially act as an angiogenic factor. The expression of apelin was examined at the RNA and protein levels in this study. Methods: We compared the expression of apelin, examined using quantitative reverse-transcription polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay and immunostaining, between pre-eclamptic patients and normotensive controls. Results: Apelin messenger RNA is significantly decreased in pre-eclamptic placentas compared with normotensive pregnancies (p < 0.05). Apelin protein levels are also lower in pre-eclamptic placentas than the controls but higher in the maternal circulation in pre-eclampsia patients. Immunohistochemical signals for apelin and its receptor APJ were detected mainly in the cytoplasm of syncytiotrophoblasts in chorionic villi and trophoblast-lineage cells in the decidua of term placentas. In early gestation, stronger APJ signals were observed at the cellular membrane. Conclusions: A functional role of the apelin--APJ system is likely in early gestation, and this raises the possibility that a dysfunctional apelin--APJ system contributes to the onset of pre-eclampsia via decreased angiogenic activity in placental implantation.

Synaptonemal complex protein 3 (SYCP3) plays a critical role in homologous chromosome pairing and recombination in meiosis, and mice deficient in this gene show infertility in males and subfertility in females. The aim of our current study was to determine whether genetic alterations in the SYCP3 gene are associated with female infertility in humans. We examined sequence variations of the SYCP3 gene in genomic DNA from 88 Japanese women with unexplained infertility and 165 samples obtained from a fertile control group. Case–control study using seven tagging single nucleotide polymorphisms revealed no significant association between common SYCP3 variants and unexplained infertility. However, only infertile women were homozygous for the minor allele of a novel rare variant in the coding region, c.666A>G (222Q>Q). The minor allele frequency was significantly higher in the infertile cohort (P< 0.05). This variant is predicted to create a cryptic splice site, although the expression of a mini-gene harboring the variant in HeLa cells or mouse testis did not demonstrate any effects on gene splicing. Our current findings therefore suggest that the c.666A>G variant in the SYCP3 gene might possibly contribute to female infertility in humans, although larger studies are needed to assess the possible effects of SYCP3 gene variation on human female infertility.