Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia

Keqing Wang, Shakil Ahmad, Meng Cai, Jillian Rennie, Takeshi Fujisawa, Fatima Crispi, James Baily, Mark R. Miller, Melissa Cudmore, Patrick W.F. Hadoke, Rui Wang, Eduard Gratacós, Irina A. Buhimschi, Catalin S. Buhimschi, Asif Ahmed

Research output: Contribution to journalArticle

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 (H2S), 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 H2S 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 H2S-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 H2S production. Conclusions-These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia. © 2013 American Heart Association, Inc.

LanguageEnglish
Pages2514-2522
Number of pages9
JournalCirculation
Volume127
Issue number25
Early online date23 May 2013
DOIs
Publication statusPublished - 25 Jun 2013

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Cystathionine gamma-Lyase
Hydrogen Sulfide
Pre-Eclampsia
Vascular Endothelial Growth Factor Receptor-1
Placentation
Human Umbilical Vein Endothelial Cells
Mothers
Fetal Development
Hypertension
Enzymes
Pregnancy
Angiogenesis Inducing Agents
Trophoblasts
Inner Ear
First Pregnancy Trimester
Vasodilator Agents
Placenta
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Intercellular Signaling Peptides and Proteins

Bibliographical note

Funding: British Heart Foundation [PG/06/114]; Medical Research Council [G0601295, G0700288]

Keywords

  • angiogenesis
  • fetal development
  • fms-like tyrosine kinase-1
  • hydrogen sulfide
  • placental growth factor
  • preeclampsia
  • vascular endothelial growth factor

Cite this

Wang, Keqing ; Ahmad, Shakil ; Cai, Meng ; Rennie, Jillian ; Fujisawa, Takeshi ; Crispi, Fatima ; Baily, James ; Miller, Mark R. ; Cudmore, Melissa ; Hadoke, Patrick W.F. ; Wang, Rui ; Gratacós, Eduard ; Buhimschi, Irina A. ; Buhimschi, Catalin S. ; Ahmed, Asif. / Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. In: Circulation. 2013 ; Vol. 127, No. 25. pp. 2514-2522.
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Wang, K, Ahmad, S, Cai, M, Rennie, J, Fujisawa, T, Crispi, F, Baily, J, Miller, MR, Cudmore, M, Hadoke, PWF, Wang, R, Gratacós, E, Buhimschi, IA, Buhimschi, CS & Ahmed, A 2013, 'Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia' Circulation, vol. 127, no. 25, pp. 2514-2522. https://doi.org/10.1161/CIRCULATIONAHA.113.001631

Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. / Wang, Keqing; Ahmad, Shakil; Cai, Meng; Rennie, Jillian; Fujisawa, Takeshi; Crispi, Fatima; Baily, James; Miller, Mark R.; Cudmore, Melissa; Hadoke, Patrick W.F.; Wang, Rui; Gratacós, Eduard; Buhimschi, Irina A.; Buhimschi, Catalin S.; Ahmed, Asif.

In: Circulation, Vol. 127, No. 25, 25.06.2013, p. 2514-2522.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia

AU - Wang, Keqing

AU - Ahmad, Shakil

AU - Cai, Meng

AU - Rennie, Jillian

AU - Fujisawa, Takeshi

AU - Crispi, Fatima

AU - Baily, James

AU - Miller, Mark R.

AU - Cudmore, Melissa

AU - Hadoke, Patrick W.F.

AU - Wang, Rui

AU - Gratacós, Eduard

AU - Buhimschi, Irina A.

AU - Buhimschi, Catalin S.

AU - Ahmed, Asif

N1 - Funding: British Heart Foundation [PG/06/114]; Medical Research Council [G0601295, G0700288]

PY - 2013/6/25

Y1 - 2013/6/25

N2 - 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 (H2S), 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 H2S 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 H2S-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 H2S production. Conclusions-These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia. © 2013 American Heart Association, Inc.

AB - 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 (H2S), 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 H2S 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 H2S-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 H2S production. Conclusions-These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia. © 2013 American Heart Association, Inc.

KW - angiogenesis

KW - fetal development

KW - fms-like tyrosine kinase-1

KW - hydrogen sulfide

KW - placental growth factor

KW - preeclampsia

KW - vascular endothelial growth factor

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U2 - 10.1161/CIRCULATIONAHA.113.001631

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