My main research interests focus on the role of oxidative stress, endothelial dysfunction and hydrogen sulphide (H2S) in the pathologies of pregnancy. Preeclampsia is a complex multifactorial disease, often complicated by fetal growth restriction. Therapeutic interventions so far remain only experimental and there is no established remedy for the treatment of preeclampsia. Placental oxidative stress, a result of deficient spiral artery remodeling, plays an important role in the pathophysiology of preeclampsia and intrauterine growth restriction. I am interested in studying signalling pathways activated by hypoxia-reoxygenation (HR) in the placenta in vivo during labour and in vitro in placental explants. Our results show the beneficial effect of antioxidant vitamins in reducing placental stress in vitro. Antiangiogenic factors secreted from malperfused placenta are instrumental in mediating maternal endothelial dysfunction and consequent symptoms of preeclampsia. I have shown that the antiangiogenic factor sFLT1 alone does not induce activation of endothelial cells, but that it acts in synergy with TNF-α to enhance the pro-inflammatory effects, by antagonising autocrine VEGF-A signalling. These findings uncover a potential mechanism of endothelial dysfunction in pre-eclampsia.
Fetal growth restriction, a leading cause of perinatal morbidity and mortality, is often associated with compromised umbilical arterial flow indicative of increased placental vascular resistance. Hydrogen sulfide, synthesised by cystathionine-γ-lyase, maintains the differentiated smooth muscle phenotype in other vascular beds, and is downregulated in growth-restricted pregnancies. I have acquired strong published and pilot evidence confirming the role of H2S in the pathology of pregnancy, linking reduced H2S production with adverse fetal outcomes. I reported the first evidence of the expression of the H2S-producing enzyme, CSE, in the smooth muscle cells of the placental stem villus arteries (SVAs) and demonstrated KATP dependent-reduction of placental vascular resistance upon exogenous administration of the H2S donor. Crucially, in placentas from intrauterine growth restricted fetuses, as well as pre-eclamptic cases that are accompanied by abnormal UA Doppler profiles, CSE expression is reduced, and this can be recapitulated by subjecting placental explants to HR. There are several projects related to the vascular resistance of SVAs and the role of CSE that I plan to address in the future, including the mechanism of fetal vasoconstriction. I aim to prove the causal link between reduced CSE expression and abnormal umbilical artery Doppler in animal models.
I have also been involved in some ground-breaking research relating to the early placental development where the conceptus develops at a low oxygen environment and it is reliant on histiotrophic support. We have recently published an important study, showing that despite the low oxygen development of the early conceptus there are no differences in the placental metabolomic profile across gestational age in terms of ATP/ADP ratio, NAD+, lactate, or glucose levels, indicating that the first trimester placenta is not compromised energetically. In addition, these data suggest that the hypoxia-induced factor, HIF-1α, is unlikely to play an appreciable role in regulating placental transcriptional activity under steady-state conditions during the first trimester in vivo, but that the pathway may be activated by fluctuations in oxygenation. These findings break the dogma about the hypoxic development of the first trimester pregnancy.
Professor John Kingdom, Mount Sinai Hospital, University of Toronto, Canada
Professor Dino Giussani, University of Cambridge, UK
Dr Lee Adamson, The Samuel Lunenfeldt Research Institute, Mount Sinai Hospital, Toronto, Canada
Professor Eric Jauniaux, University College London, London, UK
Professor Fiona Brougton-Pipkin, University of Nottingham, Nottingham, UK
Cindrova-Davies T, van Patot MT, Gardner L, Jauniaux E, Burton GJ, Charnock-Jones DS, (2015), Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development, Mol Hum Reprod, 21(3): 296-308
Cindrova-Davies T, (2014), The therapeutic potential of antioxidants, ER chaperones, NO and H2S donors, and statins for treatment of preeclampsia, Front Pharmacol, 5:119, Review
Cindrova-Davies T, Herrera EA, Niu Y, Kingdom J, Giussani DA, Burton GJ, (2013), Reduced cystathionine g-lyase and increased miR-21 are associated with increased vascular resistance in growth-restricted pregnancies: hydrogen sulfide as a placental vasodilator, Am J Pathol,182(4):1448-58
Burke KA, Jauniaux E, Burton GJ, Cindrova-Davies T, (2013), Expression and immunolocalisation of the endocytic receptors megalin and cubilin in the human yolk sac and placenta across gestation, Placenta, 34(11):1105-9
Cindrova-Davies T, Sanders DA, Burton GJ, Charnock-Jones DS, (2011), Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signaling, Cardiovasc Res, 89(3):671-9
Cindrova-Davies T, (2009), Gabor Than Award Lecture 2008: pre-eclampsia - from placental oxidative stress to maternal endothelial dysfunction, Placenta, 30 Suppl. A:S55-65
Ellery PM, Cindrova-Davies T, Jauniaux E, Ferguson-Smith AC, Burton GJ, (2009), Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta, Placenta, 30(4):329-334
Aiken C, Cindrova-Davies T, Johnson MH, (2008), Temporal and tissue variations in mitochondrial DNA levels from fertilization to birth in the mouse are influenced by reactive oxygen species, Reprod. Biomed.Online, 17(6):806-813
Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, Charnock-Jones DS, Burton GJ, (2007), NF-kB, p38 and stress activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress, Am. J. Pathol, 170: 1511-1520
Cindrova-Davies T, Yung H-W, Johns J, Spasic-Boskovic O, Korolchuk S, Jauniaux E, Burton GJ, Charnock-Jones DS, (2007), Oxidative stress, gene expression and protein changes induced in the human placenta during labor, Am. J. Pathol, 171: 1168-1179
Tjoa M-L*, Cindrova-Davies T*, Spasic-Boskovic O, Bianchi DW, Burton GJ, (2006), Trophoblastic oxidative stress and the release of cell-free feto-placental DNA, Am. J. Pathol, 169: 400-404. (* joint first authors)