Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia
Abstract
Background—: The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H 2 S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Methods and Results—: Plasma levels of H 2 S were significantly decreased in women with preeclampsia ( P <0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL -propargylglycine reduced placental growth factorproduction from first-trimester (8–12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL -propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H 2 S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL -propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H 2 S production. Conclusions—: These results imply that endogenous H 2 S is required for healthy placental vasculature and that a decrease in CSE/H 2 S activity may contribute to the pathogenesis of preeclampsia. (Circulation. 2013;127:2514-2522.)
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Inhibition of CSE activity inhibits trophoblast invasion from first trimester explants in vitro, and increases the release of anti-angiogenic factors from umbilical vein endothelial cells.
“Inhibition of CSE activity also inhibits trophoblast invasion from first trimester explants in vitro, and increases the release on anti-angiogenic factors from umbilical vein endothelial cells (559).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [559]
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Cites
Maynard, S. E., Min, J.-Y., Merchan, J., Lim, K.-H., Li, J., Mondal, S., Libermann, T. A., Morgan, J. P., Sellke, F. W., Stillman, I. E., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17189 · Cited by 4,101 · see citing works
Circulating angiogenic factors and the risk of preeclampsia
Levine, R. J., Maynard, S. E., Qian, C., Lim, K.-H., England, L. J., Yu, K. F., Schisterman, E. F., Thadhani, R., Sachs, B. P., Epstein, F. H., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa031884 · Cited by 3,720 · see citing works
Circulating angiogenic factors and the risk of preeclampsia*
(2004) · Obstetrics and Gynecology · doi:10.1097/00006250-200405000-00028 · Cited by 2,623 · see citing works
Yang, G., Wu, L., Jiang, B., Yang, W., Qi, J., Cao, K., Meng, Q., Mustafa, A. K., Mu, W., Zhang, S., et al. (2008) · Science · doi:10.1126/science.1162667 · Cited by 2,310 · see citing works
Self-citationThe vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener
Zhao, W., Zhang, J., Lu, Y., & Wang, R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.21.6008 · Cited by 1,936 · see citing works
Self-citationSoluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia
Levine, R. J., Lam, C., Qian, C., Yu, K. F., Maynard, S. E., Sachs, B. P., Sibai, B. M., Epstein, F. H., Romero, R. J., Thadhani, R., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa055352 · Cited by 1,804 · see citing works
Elrod, J. W., Calvert, J. W., Morrison, J., Doeller, J. E., Kraus, D. W., Tao, L., Jiao, X., Scalia, R. G., Kiss, L., Szabó, C., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705891104 · Cited by 1,246 · see citing works
Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia
(2006) · New England Journal of Medicine · doi:10.1056/nejmx060063 · Cited by 1,237 · see citing works
The World Health Report 2005 - make every mother and child count
Lerberghe, W. V., Manuel, A., Matthews, Z., & Wolfheim, C. (2005) · ePrints Soton (University of Southampton) · Cited by 1,015 · see citing works
The role of the spiral arteries in the pathogenesis of pre-eclampsia.
Brosens, I. A., Robertson, W. B., & Dixon, H. G. (1970) · PubMed · Cited by 894 · see citing works
Hydrogen sulfide is an endogenous stimulator of angiogenesis
Papapetropoulos, A., Pyriochou, A., Altaany, Z., Yang, G., Marazioti, A., Zhou, Z., Jeschke, M. G., Branski, L. K., Herndon, D. N., Wang, R., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908047106 · Cited by 864 · see citing works
Self-citationHydrogen sulfide is an endogenous modulator of leukocyte‐mediated inflammation
Zanardo, R. C. O., Brancaleone, V., Distrutti, E., Fiorucci, S., Cirino, G., & Wallace, J. L. (2006) · The FASEB Journal · doi:10.1096/fj.06-6270fje · Cited by 859 · see citing works
Ion exchange resins in the treatment and prophylaxis of pre-eclampsia.
Brosens, I. A., Wb, R., & Dixon, H. (1953) · PubMed · Cited by 706 · see citing works
Interactions between Trophoblast Cells and the Maternal and Fetal Circulation in the Mouse Placenta
Adamson, S. L., Lu, Y., Whiteley, K. J., Holmyard, D., Hemberger, M., Pfarrer, C., & Cross, J. C. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0773 · Cited by 617 · see citing works
Development of Structures and Transport Functions in the Mouse Placenta
Watson, E. D., & Cross, J. C. (2005) · Physiology · doi:10.1152/physiol.00001.2005 · Cited by 583 · see citing works
Make every mother and child count.
Spencer-Jones, J. (2005) · PubMed · Cited by 523 · see citing works
Ahmad, S., & Ahmed, A. (2004) · Circulation Research · doi:10.1161/01.res.0000147365.86159.f5 · Cited by 516 · see citing works
Self-citationAngiogenic Factors and Preeclampsia
Maynard, S. E., & Karumanchi, S. A. (2011) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2010.10.004 · Cited by 482 · see citing works
Thadhani, R., Mutter, W. P., Wolf, M., Levine, R. J., Taylor, R. N., Sukhatme, V. P., Ecker, J. L., & Karumanchi, S. A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031244 · Cited by 453 · see citing works
Negative Regulation of Soluble Flt-1 and Soluble Endoglin Release by Heme Oxygenase-1
Cudmore, M., Ahmad, S., Al‐Ani, B., Fujisawa, T., Coxall, H., Chudasama, K., Devey, L. R., Wigmore, S. J., Abbas‐Hanif, A., Hewett, P. W., et al. (2007) · Circulation · doi:10.1161/circulationaha.106.660134 · Cited by 421 · see citing works
Self-citationUtero-placental vascular development and placental function
Reynolds, L. P., & Redmer, D. A. (1995) · Journal of Animal Science · doi:10.2527/1995.7361839x · Cited by 418 · see citing works
Taylor, R. N., Grimwood, J., Taylor, R. S., McMaster, M., Fisher, S. J., & North, R. A. (2003) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2003.111 · Cited by 410 · see citing works
Noori, M., Donald, A. E., Angelakopoulou, A., Hingorani, A. D., & Williams, D. J. (2010) · Circulation · doi:10.1161/circulationaha.109.895458 · Cited by 361 · see citing works
Egbor, M., Ansari, T., Morris, N., Green, C. J., & Sibbons, P. (2006) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2006.00882.x · Cited by 359 · see citing works
The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats
Yan, H., Du, J., & Tang, C. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.11.081 · Cited by 336 · 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
Putative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air?
Li, L., & Moore, P. A. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.11.003 · Cited by 308 · see citing works
Preeclampsia is associated with reduced serum levels of placenta growth factor
Torry, D. S., Wang, H., Wang, T., Caudle, M. R., & Torry, R. J. (1998) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(98)70021-3 · Cited by 286 · see citing works
The Quantitative Significance of the Transsulfuration Enzymes for H 2 S Production in Murine Tissues
Kabil, Ö., Vitvitsky, V., Xie, P., & Banerjee, R. V. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3781 · Cited by 275 · see citing works
The World Health Report 2005: ``Make every mother and child count'' — including Africans
Högberg, U. (2005) · Scandinavian Journal of Public Health · doi:10.1080/14034940500217037 · Cited by 268 · see citing works
SUSPENDED ANIMATION-LIKE STATE PROTECTS MICE FROM LETHAL HYPOXIA
Blackstone, E., & Roth, M. B. (2007) · Shock · doi:10.1097/shk.0b013e31802e27a0 · Cited by 238 · see citing works
Wolf, M. S., Hubel, C. A., Lam, C. S., Sampson, M., Ecker, J. L., Ness, R. B., Rajakumar, A., Daftary, A. R., Shakir, A. S. M., Seely, E. W., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0548 · Cited by 217 · see citing works
Buhimschi, C. S., Norwitz, E. R., Funai, E. F., Richman, S. M., Guller, S. M., Lockwood, C. J., & Buhimschi, I. A. (2005) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2004.12.052 · Cited by 153 · see citing works
Self-citationHögberg, U. (2005) · Scandinavian Journal of Public Health · Cited by 143 · see citing works
Ahmad, S., Hewett, P. W., Wang, P., Al‐Ani, B., Cudmore, M., Fujisawa, T., Haigh, J. J., le Noble, F. A. C., Wang, X., Mukhopadhyay, D., et al. (2006) · Circulation Research · doi:10.1161/01.res.0000243989.46006.b9 · Cited by 140 · see citing works
Self-citationCindrova-Davies, T., Herrera, E. A., Niu, Y., Kingdom, J., Giussani, D. A., & Burton, G. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.001 · Cited by 135 · see citing works
Is inflammation the cause of pre-eclampsia?
Ramma, W., & Ahmed, A. (2011) · Biochemical Society Transactions · doi:10.1042/bst20110672 · Cited by 135 · see citing works
Self-citationPDGFB Regulates the Development of the Labyrinthine Layer of the Mouse Fetal Placenta
OHLSSON, R. I., Falck, P., Hellström, M., Lindahl, P., Boström, H., Franklin, G. C., Ährlund‐Richter, L., Pollard, J. W., Soriano, P. M., & Betsholtz, C. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9306 · Cited by 132 · see citing works
The endogenous production of hydrogen sulphide in intrauterine tissues
Patel, P., Vatish, M., Heptinstall, J., Wang, R., & Carson, R. J. (2009) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-7-10 · Cited by 126 · see citing works
Self-citationChorioallantoic Morphogenesis and Formation of the Placental Villous Tree
Cross, J. C., Simmons, D. G., & Watson, E. D. (2003) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2003.tb03212.x · Cited by 119 · see citing works
Saxena, A. R., Karumanchi, S. A., Brown, N. J., Royle, C. M., McElrath, T. F., & Seely, E. W. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.147595 · Cited by 116 · see citing works
Arterial Pressure Monitoring in Mice
Zhao, X., Ho, D. W. T., Gao, S., Hong, C., Vatner, D. E., & Vatner, S. F. (2011) · Current Protocols in Mouse Biology · doi:10.1002/9780470942390.mo100149 · Cited by 87 · see citing works
Hydrogen sulfide producing enzymes in pregnancy and preeclampsia
Holwerda, K. M., Bos, E. M., Rajakumar, A., Ris-Stalpers, C., van Pampus, M. G., Timmer, A., Erwich, J. J. H. M., Faas, M. M., van Goor, H., & Lely, A. T. (2012) · Placenta · doi:10.1016/j.placenta.2012.02.014 · Cited by 86 · see citing works
Maternal plasma soluble endoglin at 11–13 weeks' gestation in pre‐eclampsia
Foidart, J., Munaut, C., Chantraine, F., Akolekar, R., & Nicolaides, K. H. (2010) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.7621 · Cited by 84 · see citing works
Can the biology of VEGF and haem oxygenases help solve pre-eclampsia?
Ahmed, A., & Cudmore, M. (2009) · Biochemical Society Transactions · doi:10.1042/bst0371237 · Cited by 63 · see citing works
Self-citationZhuo, Y., Chen, P.-F., Zhang, A.-Z., et al. (2009) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.32.1406 · Cited by 58 · see citing works
You, X., Xu, C., Lu, J., Zhu, X., Gao, L., Cui, X., Li, Y., Gu, H., & Ni, X. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023788 · Cited by 57 · see citing works
Yanfei, W., Lin, S., Du, J., & Chaoshu, T. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.04.162 · Cited by 57 · see citing works
Savvidou, M. D., Noori, M., Anderson, J. M., Hingorani, A. D., & Nicolaides, K. H. (2008) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.6126 · Cited by 56 · see citing works
Ramma, W., Buhimschi, I. A., Zhao, G., Dulay, A. T., Nayeri, U. A., Buhimschi, C. S., & Ahmed, A. (2012) · Angiogenesis · doi:10.1007/s10456-012-9261-5 · Cited by 51 · see citing works
Self-citationPlacental Abnormalities and Preeclampsia in Trisomy 13 Pregnancies
Chen, C. (2009) · Taiwanese Journal of Obstetrics and Gynecology · doi:10.1016/s1028-4559(09)60028-0 · Cited by 39 · see citing works
Hydrogen Sulfide: Redox Metabolism and Signaling
Banerjee, R. V. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.3912 · Cited by 36 · see citing works
The Effect of Hydroxylamine on KATP Channels in Vascular Smooth Muscle and Underlying Mechanisms
Tang, G., Wu, L., & Wang, R. (2005) · Molecular Pharmacology · doi:10.1124/mol.104.008953 · Cited by 17 · see citing works
Self-citationNon-endothelial cell endothelin-B receptors limit neointima formation following vascular injury
Kirkby, N. S., Duthie, K., Miller, E., et al. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs137 · Cited by 12 · see citing works
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Research works printed but not linked: 2
- Kabil O, Vitvitsky V, Xie P, Banerjee R. The quantitative significance of the transsulfuration enzymes for H2S production in murine tissues. Antioxid Redox Signal. 2011;15:363-372.
- Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu. 1972;1:177-191.
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- Authors
- Wang, K., Ahmad, S., Cai, M., Rennie, J., Fujisawa, T., Crispi, F., Baily, J., Miller, M. R., Cudmore, M., Hadoke, P. W. F., Wang, R., Gratacós, E., Buhimschi, I. A., Buhimschi, C. S., & Ahmed, A.
- Affiliations
- Nationwide Children's Hospital (US)
- ORCID
- Venue
- Circulation
- Published
- 2013-06-25
- Volume
- 127
- Issue
- 25
- Pages
- 2514-2522
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W1981512919
- Cited by
- 256
- References
- 54
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 14 · 2023: 20 · 2022: 28 · 2021: 18 · 2020: 25 · 2019: 15 · 2018: 15 · 2017: 25 · 2016: 17 · 2015: 23 · 2014: 30 · 2013: 7
- FWCI
- 28.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Aston Publications Explorer (Aston University) (submittedVersion)
- Funders
- British Heart Foundation (PG/06/114)
- Medical Research Council (MR/K024868/1)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
- Keywords
- preeclampsia, cystathionine gamma-lyase, hydrogen sulfide, maternal hypertension, placental abnormalities, angiogenic imbalance, placental growth factor, trophoblast invasion, soluble fms-like tyrosine kinase-1, soluble endoglin, placental vasculature, fetal growth restriction, GYY4137, DL-propargylglycine, placental labyrinth
- MeSH terms
- Endoglin, Placenta Growth Factor, Adolescent, Adult, Alkynes, Animals, Cells, Cultured, Cystathionine gamma-Lyase, Disease Models, Animal, Endothelium, Vascular, Female, Glycine, Humans, Hydrogen Sulfide, Hypertension, Mice, Inbred C57BL, Morpholines, Organ Culture Techniques, Organothiophosphorus Compounds, Placenta, Placenta Diseases, Pre-Eclampsia, Pregnancy, Pregnancy Complications, Cardiovascular, Pregnancy Proteins, Pregnancy, Animal, Receptors, Cell Surface, Antigens, CD, Neovascularization, Physiologic, Vascular Endothelial Growth Factor Receptor-1, Fetal Development, Mice, Young Adult
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