title: 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 (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.
  
  
  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.
authors.affiliation: Vascular Medicine Unit, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: Meng
authors.initials: M
authors.lastname: Cai
authors.forename: Jillian
authors.initials: J
authors.lastname: Rennie
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Fatima
authors.initials: F
authors.lastname: Crispi
authors.forename: James
authors.initials: J
authors.lastname: Baily
authors.forename: Mark R
authors.initials: MR
authors.lastname: Miller
authors.forename: Melissa
authors.initials: M
authors.lastname: Cudmore
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Eduard
authors.initials: E
authors.lastname: Gratacós
authors.forename: Irina A
authors.initials: IA
authors.lastname: Buhimschi
authors.forename: Catalin S
authors.initials: CS
authors.lastname: Buhimschi
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D000293:Adolescent; D000328:Adult; D000480:Alkynes / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D004195:Disease Models, Animal; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000187:drug effects / Q000502:physiology; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000502:physiology; D009924:Organ Culture Techniques; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010922:Placenta Diseases / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000503:physiopathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D011257:Pregnancy Proteins / Q000378:metabolism; D011270:Pregnancy, Animal; D011956:Receptors, Cell Surface / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D000480:Alkynes; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; D000072483:Placenta Growth Factor; C009055:propargylglycine; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D003542:Cystathionine gamma-Lyase; D005998:Glycine; D006862:Hydrogen Sulfide
keywords: angiogenesis; fetal development; fms-like tyrosine kinase-1; hydrogen sulfide; placental growth factor; preeclampsia; vascular endothelial growth factor