Graham J. Burton

Placental oxidative stress: from miscarriage to preeclampsia.

Objective: To review the role of oxidative stress in two common placental-related disorders of pregnancy, miscarriage and preeclampsia. Methods: Review of published literature. Results: Miscarriage and preeclampsia manifest at contrasting stages of pregnancy, yet both have their roots in deficient trophoblast invasion during early gestation. Early after implantation, endovascular trophoblast cells migrate down the lumens of spiral arteries, and are associated with their physiological conversion into flaccid conduits. Initially these cells occlude the arteries, limiting maternal blood flow into the placenta. The embryo therefore develops in a low oxygen environment, protecting differentiating cells from damaging free radicals. One embryogenesis is complete, the maternal intervillous circulation becomes fully established, and intraplacental oxygen concentration rises threefold. Onset of the circulation is normally a progressive periphery-center phenomenon, and high levels of oxidative stress in the periphery may induce formation of the chorion laeve. If trophoblast invasion is severly impaired, plugging of the spiral arteries is incomplete, and onset of the maternal intervillous circulation is premature and widespread throughout the placenta. Syncytiotrophoblastic oxidative damage is extensive, and likely a major contributory factor to miscarriage. Between these two extremes will be found differing degrees of trophoblast invasion compatible with ongoing pregnancy but resulting in deficient conversion of the spiral arteries and an ischemia-reperfusion-type pehnomenon. Placental perfusion will be impaired to a greater or lesser extent, generating commensurate placental oxidative stress that is a major contributory factor to preeclampsia. Conclusion: Miscarriage, missed miscarriage, and early- and late-onset preeclampsia represent a spectrum of disorders secondary to deficient trophoblast invasion.

Evidence for oxygen-derived free radical mediated damage to first trimester human trophoblast in vitro

Summary We have found that, despite considerable experimentation with conditions, we are unable to maintain first trimester syncytiotrophoblast in a viable state in organ culture (conventional conditions i.e. in buffered culture medium supplemented with serum, maintained at 37°C/21% oxygen/5% carbon dioxide). Evidence for syncytiotrophoblastic degeneration includes: parallel release of LDH and HCG, widespread NΣ-Dansyl-1-Lysine uptake, indicating cell death, and extensive vacuolation observed via electron microscopy. These results suggest syncytial death occurs within hours of culture initiation. Despite this the cytotrophoblasts and stromal cell populations showed good viability for a number of days as shown by BrdU incorporation. When investigating the effect of oxygen tension on tissue survival we found that lipid peroxidation was considerably increased under ambient (21%) rather than low (2.5%) oxygen conditions. Furthermore, keeping early villous tissue at 2.5% oxygen reduced the rate of HCG as well as LDH release and also improved the ultrastructural appearance of the syncytiotrophoblast. We subsequently discovered that mitochondrial activity within the syncytiotrophoblast declined to virtually zero within six hours of cultureat 21% O2 but was retained for this period at 2.5% O2. Second trimester tissue, however, showed mitochondrial activity following 6 hours of culture at 21% O2. These results suggest that the syncytiotrophoblast is acutely sensitive to oxygen during the first trimester but becomes more resistant by 14 weeks gestational age, probably due to an increase in the capacity of the mechanisms which defend cells against oxidative stress.