Dysregulation of Hydrogen Sulfide (H2S) Producing Enzyme Cystathionine γ-lyase (CSE) Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia
Background—The exact etiology of preeclampsia is unknown, but there is a growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulphide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE, also know as CTH), is a pro-angiogenic vasodilator. We hypothesised 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 PCR and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine (PAG) reduced placenta growth factor (PlGF) production 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 (HUVEC) by siRNA increased the release of soluble fms-Like tyrosine kinase-1 (sFlt-1) and soluble endoglin, (sEng) as assessed by ELISA while adenoviral-mediated CSE overexpression in HUVEC inhibited their release. Administration of PAG to pregnant mice induced hypertension, liver damage, and promoted abnormal labyrinth vascularisation in the placenta and decreased fetal growth. Finally, a slow releasing H2S-generating compound, GYY4137 inhibited circulating sFlt-1 and sEng levels and restored fetal growth in mice that was compromised by PAG treatment demonstrating that the effect of CSE inhibitor was due to inhibition of H2S production.
Conclusions—These results imply that endogenous H2S is required for healthy placental vasculature and a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.
- Hydrogen Sulfide
- placenta growth factor
- soluble Endoglin
- endothelial cell
- Received February 5, 2013.
- Revision received March 20, 2013.
- Accepted April 12, 2013.