Placental hypoxia, endoplasmic reticulum stress and maternal endothelial sensitisation by sFLT1 in pre-eclampsia
Journal of Reproductive Immunology
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Charnock-Jones, S. (2015). Placental hypoxia, endoplasmic reticulum stress and maternal endothelial sensitisation by sFLT1 in pre-eclampsia. Journal of Reproductive Immunology https://doi.org/10.1016/j.jri.2015.07.004
The human placenta is a multifunctional organ that grows and adapts to increasing fetal demand and fluctuations in the intrauterine environment. It is subjected to physiological and pathological changes in local oxygenation, both of which induce adaptive changes. In early pregnancy a low PO2 is the normal physiological state and this is not hypoxic—there is no perturbation of ATP/ADP ratios and, if the placenta is sampled very rapidly, little HIF1α is detected in human first-trimester placental villi. Nonetheless, HIF1α can be increased and activated by culture. However, the placenta does show evidence of stress under pathological conditions. For example, in cases of pre-eclampsia where delivery by caesarean section is necessitated for maternal well-being before 34 weeks’ gestation, placental endoplasmic reticulum stress is evident. Cases delivered ≥34 weeks are indistinguishable from normal term controls. One consequence of placental stress, whether oxidative, related to the endoplasmic reticulum or immunological, is that factors are released into the maternal circulation, which affects the endothelium, leading to the maternal syndrome. Soluble FLT1 may contribute directly to this and the most likely mechanism is direct action on the maternal endothelium. sFLT1 is able to form a heterodimer with cell surface VEGF receptors and is therefore able to have a dominant negative effect (in addition to acting as a competitive inhibitor by simply binding vascular endothelial growth factor A [VEGFA] and placental growth factor [PlGF]). This leads in vitro to the sensitisation of endothelial cells to low levels of TNFα.
hypoxia, ER stress, unfolded protein response, sFLT1, pre-eclampsia
This work was supported by the Wellcome Trust (084804/2/08/Z) and the NIHR Cambridge Comprehensive Biomedical Research Centre.
External DOI: https://doi.org/10.1016/j.jri.2015.07.004
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248943
Creative Commons Attribution 4.0
Licence URL: http://creativecommons.org/licenses/by/4.0/
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