Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia
Open accessAbstract
The pregnancy complications of unexplained intrauterine growth restriction and early onset preeclampsia are thought to share a common aetiology in placental malperfusion secondary to deficient maternal spiral artery conversion. A key question is whether the contrasting clinical manifestations reflect different placental pathologies, or whether they are due to altered maternal responses to a common factor derived from the placenta. Recently, molecular evidence of protein synthesis inhibition secondary to endoplasmic reticulum stress has provided an explanation for the small placental phenotype in both conditions. However, other pathways activated by more severe endoplasmic reticulum stress are only observed in placentas from pregnancies associated with early onset preeclampsia. Here, we review the literature and conclude that there is evidence of greater maternal vascular compromise of the placenta in these cases. We speculate that in cases of normotensive intrauterine growth restriction the placental pathology is centred predominantly around endoplasmic reticulum stress, whereas in cases complicated by preeclampsia oxidative stress is further superimposed. This causes the release of a potent mix of pro-inflammatory cytokines, anti-angiogenic factors and trophoblastic aponecrotic debris into the maternal circulation that causes the peripheral syndrome. Maternal and fetal constitutional factors may modulate how the placenta responds to the maternal vascular insult, and how the mother is affected by the placental factors released. However, the principal conclusion is that the difference between these two conditions lies in the severity of the initiating deficit in spiral arterial conversion, and the relative degrees of endoplasmic reticulum stress and oxidative stress induced in the placenta as a result.
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Cites
Free radicals in biology and medicine
Gutteridge, J. M. C. (1991) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(91)90478-o · Cited by 17,178 · see citing works
Latest Advances in Understanding Preeclampsia
Redman, C. W., & Sargent, I. L. (2005) · Science · doi:10.1126/science.1111726 · Cited by 2,607 · see citing works
Endoplasmic reticulum stress: cell life and death decisions
Xu, C. (2005) · Journal of Clinical Investigation · doi:10.1172/jci26373 · Cited by 2,260 · see citing works
From endoplasmic-reticulum stress to the inflammatory response
Zhang, K., & Kaufman, R. J. (2008) · Nature · doi:10.1038/nature07203 · Cited by 2,010 · see citing works
KHONG, T. Y., DE WOLF, F., ROBERTSON, W. B., & BROSENS, I. (1986) · BJOG: An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1986.tb07830.x · Cited by 1,591 · see citing works
Yoshida, H. (2007) · The FEBS Journal · doi:10.1111/j.1742-4658.2007.05639.x · Cited by 1,086 · see citing works
Oxidative protein folding in eukaryotes
Tu, B. P., & Weissman, J. S. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200311055 · Cited by 1,041 · see citing works
Free Radicals in Biology and Medicine
Kovacic, P. (1986) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600750133 · Cited by 982 · see citing works
Meekins, J. W., Pijnenborg, R., HANSSENS, M. C. A. J. A., McFadyen, I., & van Asshe, A. (1994) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1994.tb13182.x · Cited by 901 · see citing works
Oxidative stress in the placenta
Myatt, L., & Cui, X.-L. (2004) · Histochemistry and Cell Biology · doi:10.1007/s00418-004-0677-x · Cited by 803 · see citing works
Oxidative Stress in the Pathogenesis of Preeclampsia
Hubel, C. A. (1999) · Proceedings of The Society for Experimental Biology and Medicine · doi:10.1046/j.1525-1373.1999.d01-139.x · Cited by 673 · see citing works
Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway
Cullinan, S. B., & Diehl, J. A. (2006) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2005.09.018 · Cited by 554 · see citing works
The myometrial junctional zone spiral arteries in normal and abnormal pregnancies
Brosens, J. J., Pijnenborg, R., & Brosens, I. A. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.127305 · Cited by 536 · see citing works
Ishihara, N., Matsuo, H., Murakoshi, H., Laoag‐Fernandez, J. B., Samoto, T., & Maruo, T. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.119176 · Cited by 509 · see citing works
Placental Debris, Oxidative Stress and Pre-eclampsia
Redman, C. W. G., & Sargent, I. L. (2000) · Placenta · doi:10.1053/plac.2000.0560 · Cited by 508 · see citing works
Villar, J., Carroli, G., WOJDYLA, D. M., Abalos, E. J., Giordano, D., Ba’aqeel, H., Farnot, U., Bergsjø, P., Bakketeig, L. S., Lumbiganon, P., et al. (2006) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2005.10.813 · Cited by 464 · see citing works
Ness, R. B., & Sibai, B. M. (2006) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2005.07.049 · Cited by 460 · see citing works
Fetal growth retardation and the arteries of the placental bed
Brosens, I., Dixon, H. G., & Robertson, W. B. (1977) · BJOG: An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1977.tb12676.x · Cited by 430 · see citing works
Placental apoptosis in preeclampsia
Allaire, A. D. (2000) · Obstetrics and Gynecology · doi:10.1016/s0029-7844(00)00895-4 · Cited by 416 · see citing works
Goswami, D., Tannetta, D., Magee, L. A., Fuchisawa, A., Redman, C. W. G., Sargent, I. L., & von Dadelszen, P. (2005) · Placenta · doi:10.1016/j.placenta.2004.11.007 · Cited by 402 · see citing works
Hung, T., Skepper, J. N., Jones, D. S., & Burton, G. J. (2002) · Circulation Research · doi:10.1161/01.res.0000024411.22110.aa · Cited by 397 · see citing works
Self-citationYung, H.-W., Calabrese, S., Hynx, D., Hemmings, B. A., Cetin, I., Charnock-Jones, D. S., & Burton, G. J. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.071193 · Cited by 388 · see citing works
Self-citationProtein Kinase Bα/Akt1 Regulates Placental Development and Fetal Growth
Yang, Z.-Z., Tschopp, O., Hemmings-Mieszczak, M., Feng, J., Brodbeck, D., Perentes, E., & Hemmings, B. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302847200 · Cited by 384 · see citing works
Increased placental apoptosis in intrauterine growth restriction
SMITH, S. C. H., Baker, P. N., & SYMONDS, E. M. (1997) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(97)70081-4 · Cited by 374 · see citing works
Gerretsen, G., Huisjes, H. J., & Elema, J. D. (1981) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1981.tb02222.x · Cited by 370 · see citing works
Is oxidative stress the link in the two-stage model of pre-eclampsia?
Roberts, J. M., & Hubel, C. A. (1999) · The Lancet · doi:10.1016/s0140-6736(99)80002-6 · Cited by 364 · see citing works
Urinary Placental Growth Factor and Risk of Preeclampsia
Levine, R. J. (2005) · JAMA · doi:10.1001/jama.293.1.77 · Cited by 335 · see citing works
Oxidative Stress, Gene Expression, and Protein Changes Induced in the Human Placenta during Labor
Cindrová‐Davies, T., Yung, H. W., Johns, J., Spasić-Bošković, O., Korolchuk, S., Jauniaux, E. R. M., Burton, G. J., & Jones, D. S. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070528 · Cited by 296 · see citing works
Self-citationHung, T., Skepper, J. N., & Burton, G. J. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61778-6 · Cited by 289 · see citing works
Self-citationIncreased placental apoptosis in pregnancies complicated by preeclampsia
Leung, D. N., Smith, S. C., To, K. F., Sahota, D. S., & Baker, P. N. (2001) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2001.112906 · Cited by 281 · see citing works
Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression
Brewer, J. W., Hendershot, L. M., Sherr, C. J., & Diehl, J. A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.15.8505 · Cited by 276 · see citing works
Placental mitochondria as a source of oxidative stress in pre-eclampsia
Wang, Y., & Walsh, S. W. (1998) · Placenta · doi:10.1016/s0143-4004(98)90018-2 · Cited by 262 · see citing works
Placental Phenotypes of Intrauterine Growth
Sibley, C. P., Turner, M. A., Cetin, I., Ayuk, P. T.-Y., Boyd, C. A. R., D'Souza, S. W., Glazier, J. D., Greenwood, S. L., Jansson, T., & Powell, T. L. (2005) · Pediatric Research · doi:10.1203/01.pdr.0000181381.82856.23 · Cited by 250 · see citing works
Shibata, E., Rajakumar, A., Powers, R. W., Larkin, R., Gilmour, C., Bodnar, L. M., Crombleholme, W. R., Ness, R. B., Roberts, J. M., & Hubel, C. A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1955 · Cited by 240 · see citing works
SHEPPARD, B. L., & Bonnar, J. (1976) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1976.tb00781.x · Cited by 232 · see citing works
Trophoblastic Oxidative Stress and the Release of Cell-Free Feto-Placental DNA
Tjoa, M. L., Cindrová‐Davies, T., Spasić-Bošković, O., Bianchi, D. W., & Burton, G. J. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.060161 · Cited by 225 · see citing works
Self-citationTakagi, Y., Nikaido, T., Toki, T., Kita, N., Kanai, M., Ashida, T., Ohira, S., & Konishi, I. (2004) · Virchows Archiv · doi:10.1007/s00428-003-0903-2 · Cited by 225 · see citing works
Cerebral ischemia and the unfolded protein response
DeGracia, D. J., & Montie, H. L. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02703.x · Cited by 224 · see citing works
Hung, T., Jones, D. S., Skepper, J. N., & Burton, G. J. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63192-6 · Cited by 209 · see citing works
Self-citationCindrová‐Davies, T., Spasić-Bošković, O., Jauniaux, E. R. M., Jones, D. S., & Burton, G. J. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.061035 · Cited by 190 · see citing works
Self-citationHyperuricemia and xanthine oxidase in preeclampsia, revisited
Many, A., Hubel, C. A., & Roberts, J. M. (1996) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(96)70410-6 · Cited by 187 · see citing works
A STUDY OF THE SPIRAL ARTERIES OF THE DECIDUA BASALIS IN NORMOTENSIVE AND HYPERTENSIVE PREGNANCIES
Brosens, I. A. (1964) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1964.tb04270.x · Cited by 147 · see citing works
Cindrová‐Davies, T. (2009) · Placenta · doi:10.1016/j.placenta.2008.11.020 · Cited by 145 · see citing works
The Human Placental Bed Revisited
Lyall, F. (2002) · Placenta · doi:10.1053/plac.2002.0850 · Cited by 143 · see citing works
Mayhew, T. M., Manwani, R., Ohadike, C., Wijesekara, J., & Baker, P. N. (2006) · Placenta · doi:10.1016/j.placenta.2006.02.011 · Cited by 128 · see citing works
Cell-free fetal DNA in the plasma of pregnant women with severe fetal growth restriction.
Sekizawa, A., Jimbo, M., Saito, H., et al. (2003) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2003.27 · Cited by 125 · see citing works
Laivuori, H. M., Gallaher, M. J., Collura, L. A., Crombleholme, W. R., Marković, N., Rajakumar, A., Hubel, C. A., Roberts, J. M., & Powers, R. W. (2006) · Molecular Human Reproduction · doi:10.1093/molehr/gal064 · Cited by 117 · see citing works
Chaiworapongsa, T., Espinoza, J., Gotsch, F., Kim, Y. M., Kim, G. J., Gonçalves, L. F., Edwin, S. S., Kusanovic, J. P., Erez, O., Than, N. G., et al. (2008) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767050701832833 · Cited by 115 · see citing works
Oxidative stress in the pathogenesis of preeclampsia.
Hubel, C. A. (1999) · PubMed · doi:10.1177/153537029922200305 · Cited by 106 · see citing works
Does endothelial cell activation occur with intrauterine growth restriction?
Johnson, M. R., Anim‐Nyame, N., Johnson, P., Sooranna, S. R., & Steer, P. J. (2002) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2002.01045.x · Cited by 76 · see citing works
A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia
Soleymanlou, N., Wu, Y., Wang, J., Todros, T., Ietta, F., Jurisicova, A., Post, M., & Caniggia, I. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401593 · Cited by 68 · see citing works
El‐Sayed, A. M. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816509-6.00009-4 · Cited by 66 · see citing works
Shibata, E., Hubel, C. A., Powers, R. W., von Versen‐Höynck, F., Gammill, H. S., Rajakumar, A., & Roberts, J. M. (2008) · Placenta · doi:10.1016/j.placenta.2008.07.001 · Cited by 60 · see citing works
Burton, G. J., & Hung, T. (2003) · Fetal and Maternal Medicine Review · doi:10.1017/s0965539503001049 · Cited by 52 · see citing works
Self-citationVaiman, D., Mondon, F., Garcès-Duran, A., Mignot, T.-M., Robert, B., Rebourcet, R., Jammes, H., Chelbi, S. T., Quetin, F., Marceau, G., et al. (2005) · BMC Genomics · doi:10.1186/1471-2164-6-111 · Cited by 48 · see citing works
Sahlin, L., Östlund, E., Wang, H., Holmgren, A., & Fried, G. M. (2000) · Placenta · doi:10.1053/plac.2000.0554 · Cited by 34 · see citing works
Choi, S., Oh, S., Kim, J., Sadovsky, Y., & Roh, C. (2007) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2006.08.029 · Cited by 33 · see citing works
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Steegers, E. A., von Dadelszen, P., Duvekot, J. J., & Pijnenborg, R. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60279-6 · Cited by 2,850 · see citing works
Pre-eclampsia part 1: current understanding of its pathophysiology
Chaiworapongsa, T., Chaemsaithong, P., Yeo, L., & Romero, R. (2014) · Nature Reviews Nephrology · doi:10.1038/nrneph.2014.102 · Cited by 956 · see citing works
Placental Origins of Chronic Disease
Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717 · see citing works
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Sultana, Z., Maiti, K., Aitken, J., Morris, J., Dedman, L., & Smith, R. (2017) · American Journal of Reproductive Immunology · doi:10.1111/aji.12653 · Cited by 288 · see citing works
Romero, R., Erez, O., Hüttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B. H., & Grossman, L. I. (2017) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2017.06.003 · Cited by 253 · see citing works
Collins, S. L., Birks, J. S., Stevenson, G. N., Papageorghiou, A. T., Noble, J. A., & Impey, L. (2012) · Ultrasound in Obstetrics & Gynecology · doi:10.1002/uog.10149 · Cited by 55 · see citing works
Szalai, G., Romero, R., Chaiworapongsa, T., Xu, Y., Wang, B., Ahn, H., Xu, Z., Chiang, P. J., Sundell, B., Wang, R., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119547 · Cited by 46 · see citing works
Szabo, S., Mody, M., Romero, R., Xu, Y., Karaszi, K., Mihalik, N., Xu, Z., Bhatti, G., Fule, T., Hupuczi, P., et al. (2015) · Pathology & Oncology Research · doi:10.1007/s12253-014-9872-9 · Cited by 45 · see citing works
Collins, S. L., Welsh, A. W., Impey, L., Noble, J. A., & Stevenson, G. N. (2017) · PLOS ONE · doi:10.1371/journal.pone.0178675 · Cited by 25 · see citing works
- Authors
- Burton, G. J., Yung, H.-W., Cindrova-Davies, T., & Charnock-Jones, D. S.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Burton, G.J.
- Venue
- Placenta
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 30
- Pages
- 43-48
- ISSN
- 0143-4004 (ISSN-L)
- PMC
- PMC2684656
- OpenAlex
- W2004055816
- Cited by
- 502
- References
- 57
- Citations by year
- 2026: 21 · 2025: 19 · 2024: 30 · 2023: 34 · 2022: 38 · 2021: 37 · 2020: 40 · 2019: 31 · 2018: 26 · 2017: 36 · 2016: 25 · 2015: 28 · 2014: 36 · 2013: 20 · 2012: 26
- FWCI
- 20.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Placenta (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (069027/Z/02/Z)
- National Institute for Health and Care Research
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
- Keywords
- endoplasmic reticulum stress, oxidative stress, fetal growth restriction, early-onset preeclampsia, placental malperfusion, inflammatory cytokines, anti-angiogenic factors, trophoblast apoptosis, placental pathology
- MeSH terms
- Endoplasmic Reticulum, Female, Fetal Growth Retardation, Humans, Placental Insufficiency, Pre-Eclampsia, Pregnancy, Uterus, Signal Transduction, Protein Folding, Oxidative Stress
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