Pre-eclampsia is a principal cause of maternal morbidity and mortality, affecting 5-10% of first pregnancies worldwide. Manifestations include increased blood pressure, proteinuria, coagulopathy and peripheral and cerebral oedema. Although the aetiology and pathogenesis remain to be elucidated, the placenta is undoubtedly involved, as termination of pregnancy eradicates the disease. Here we have cloned a complementary DNA from human placental messenger RNA encoding a precursor protein of 121 amino acids which gives rise to a mature peptide identical to the neuropeptide neurokinin B (NKB) of other mammalian species. In female rats, concentrations of NKB several-fold above that of an animal 20 days into pregnancy caused substantial pressor activity. In human pregnancy, the expression of NKB was confined to the outer syncytiotrophoblast of the placenta, significant concentrations of NKB could be detected in plasma as early as week 9, and plasma concentrations of NKB were grossly elevated in pregnancy-induced hypertension and pre-eclampsia. We conclude that elevated levels of NKB in early pregnancy may be an indicator of hypertension and pre-eclampsia, and that treatment with certain neurokinin receptor antagonists may be useful in alleviating the symptoms.

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Placental neurokinin B appears to be post-translationally modified by phosphocholine (PC) attached to the aspartyl side chain at residue 4 of the mature peptide. Corticotrophin releasing factor (CRF) was found to be expressed by the rat placenta with the main secreted forms being phosphocholinated proCRF+/− one or two polysaccharide moieties. A combination of high-pressure liquid chromatography (HPLC) and two-site immunometric analysis suggested that PC was also attached to the placental precursors of adrenocorticotrophin, hemokinin, activin and follistatin. However, the fully processed forms of rat placental activin and CRF were free of PC. Formerly, the parasitic filarial nematodes have used PC as a post-translational modification, attached via the polysaccharide moiety of certain secretory glycoproteins to attenuate the host immune system allowing parasite survival, but it is the PC group itself which endows the carrier with the biological activity. The fact that treatment of proCRF peptides with phospholipase C but not endoglycosidase destroyed PC immunoreactivity suggested a simpler mode of attachment of PC to placental peptides than that used by nematodes. Thus, it is possible that by analogy the placenta uses its secreted phosphocholinated hormones to modulate the mother's immune system and help protect the placenta from rejection.

Di Iorio R, Marinoni E, Anceschi MM, Emiliani S, Letizia C and Cosmi EV (1996)

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Objectives: Many of the maternal serum markers used in prenatal screening have been developed or evolved based on serendipity. This study determines the feasibility of developing a genetic profile of placental gene expression during early pregnancy; such a gene repertoire may serve as a tool for identifying novel secreted markers. Methods: RNA fingerprinting was used to produce a differential expression map in normal aborted placentae of weeks 9 and 13. Results: Out of 212 gene expression differences, 115 were up-regulated at week 9 and the remaining 97 up-regulated at week 13. Ninety-four were found to be previously characterised genes and 118 were expressed sequence tags or novel genes. Seven of the known genes were found to be secreted proteins and included well-characterised pregnancy markers. mRNA levels of these secreted proteins were found to correlate with levels found in maternal serum. Conclusion: This approach enabled the identification of known secreted markers leaving open the possibility of finding new markers. With the human genome project nearing completion, it will be vital to use a systematic approach to understand the actual pattern of gene expression during pregnancy. This will also allow a more ordered and precise identification of novel prenatal diagnostic markers.