The exact aetiology of preeclampsia is unknown, but there is a good association with an imbalance in angiogenic growth factors and abnormal placentation (Ahmad & Ahmed, 2004). Hydrogen sulphide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is pro-angiogenic vasodilator (Yang et al, 2008; Papapetropoulos et al, 2009). We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Plasma levels of H2S were significantly decreased in preeclamptic women (p<0.01), which was associated with reduced CSE message and protein expression in human placenta as determined by real-time PCR and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine (PAG) in first trimester (8-12 weeks gestation) human placental explants had reduced placenta growth factor (PlGF) production as assessed by ELISA and inhibited trophoblast invasion in vitro. Endothelial CSE knockdown by siRNA transfection increased the endogenous release of soluble fms-Like tyrosine kinase-1 (sFlt-1) and soluble endoglin, (sEng) from human umbilical vein endothelial cells while adenoviral-mediated CSE overexpression 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 that was compromised by PAG-treatment demonstrating that the effect of CSE inhibitor was due to inhibition of H2S production. These results imply that endogenous H2S is required for healthy placental vasculature and a decrease in of CSE/ H2S activity may contribute to the pathogenesis of preeclampsia.
37th Congress of IUPS (Birmingham, UK) (2013) Proc 37th IUPS, PCC394
Poster Communications: Dysregulation of hydrogen sulfide producing enzyme cystathionine ╬│-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia
K. Wang1, W. Abu-Alkhier1,5, S. Ahmad1, M. Cai1, J. Rennie2, T. Fujisawa2, F. Crispi3, J. Baily2, R. Wang4, E. Gratacós3, I. Buhimschi5, C. Buhimschi5, A. Ahmed1
1. Vascular Biology Unit, Aston University, Birmingham, United Kingdom. 2. Gustav Born Centre for Vascular Biology, University of Edinburgh, Edinburgh, United Kingdom. 3. Department of Maternal-Fetal Medicine, University of Barcelona, Barcelona, Spain. 4. Lakehead University, Thunder Bay, Ontario, Canada. 5. Yale School of Medicine, Yale University, New Haven, Connecticut, United States.
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Where applicable, experiments conform with Society ethical requirements.