Gabor Than Award Lecture 2008: pre-eclampsia - from placental oxidative stress to maternal endothelial dysfunction.
Pre-eclampsia is the most important complication of human pregnancy worldwide and a major contributor to maternal and fetal morbidity and mortality. Strong evidence exists that generation of placental oxidative stress, secondary to deficient spiral artery remodelling, is a key intermediary event, triggering the secretion of a mixture of placental factors that culminate in an enhanced maternal inflammatory response. Reactive oxygen species (ROS) have been recognised as secondary messengers in intracellular signalling cascades. Experiments studying placental ischaemia-reperfusion in vitro or in vivo during labour provide strong evidence suggesting that oxidative stress and ROS production can activate downstream stress-signalling pathways, p38 and SAPK/JNK MAPK, and the pro-inflammatory NF-kappaB signalling pathway, culminating in the release of inflammatory mediators, apoptotic debris, anti-angiogenic factors and other mediators, which then stimulate a maternal inflammatory reaction that manifests in endothelial dysfunction and the symptoms of pre-eclampsia. Addition of anti-oxidants or blocking the stress or inflammatory pathways in vitro attenuates these effects and opens possibilities for therapeutic intervention.
Cindrova-Davies
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Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK. tc269@cam.ac.uk
D000975:Antioxidants / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology; D004727:Endothelium / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010920:Placenta / Q000098:blood supply; D011225:Pre-Eclampsia / Q000209:etiology* / Q000503:physiopathology; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000502:physiology
D000975:Antioxidants; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D051057:Proto-Oncogene Proteins c-akt