Expression and regulation of vasoactive substances, sex steroids and their receptors in placenta during normal pregnancy and preeclampsia

Abstract: Despite intense studies preeclampsia remains enigmatic and a major cause of maternal and fetal morbidity and mortality. It is now widely accepted that the placenta has a central role in preeclampsia; delivery of the placenta is the only known cure. Its manifestations are considered secondary to inadequate trophoblast invasion of the uterine spiral arteries, which leads to placenta] ischemia and further to the devastating multisystem disorder of the mother and often the fetus. The syndrome is characterised by increased vasoconstriction and endothelial dysfunction. Several biochemical changes in the placenta are evident. The nitric oxide (NO) system as well as the sex steroid hormones, estrogen and progesterone have been implicated in the aetiology of preeclampsia. However the role and the regulation of these substances is still not clear. The aim of the present thesis was to study some of the genes expressed in the placenta that could be involved in the pathophysiology of preeclampsia and/or intrauterine growth restriction (IUGR). Consecutive biopsies of fresh placentas were collected from normal and preeclampsia -complicated placentas. A placental tissue in vitro model was set up for experiments. For mRNA studies of endothelin-1, c-fos and c-jun, the progesterone receptor (PR) and the estrogen receptor (ER) we used a solution hybridisation method, which showed elevated expression of ET-1 and c-fos in IUGR placentas. The c-jun mRNA was significantly higher in the groups with preeclampsia and/or IUGR compared to controls. Furthermore, in situ hybridisation of the PR demonstrated it to be localised in endothelium, in fetal lymphocytes of placental capillaries and occasionally in matemal mononuclear cells. The PR protein content in the different groups showed that the level was decreased in severe preeclampsia but increased in mild preeclampsia compared to healthy controls. Measurement of progesterone content in placental tissue explants showed that addition of the antiprogestin RU-486 decreased the level of progesterone in the healthy placentas, whereas no such decrease was seen in the placentas from patients with preeclampsia after RU-486 treatment. Furthermore the effect of the antiestrogen, ICI 182,780 was different in placentas from control and preeclamptic patients. eNOS immunosignal recorded by immunohistochemistry and confocal microscopy was significantly increased in the syncytiotrophoblasts of healthy placentas after ICI treatment but decreased in the preeclampsia placentas. We suggest that an inadequate supply of progesterone, a deficiency in the mechanism of action of progesterone andlor an altered balance between the sex steroids produced by the placenta could influence not only the immune system but also the NO pathway and hereby contribute to several changes characteristic of preeclampsia.