Dysregulation of Hydrogen Sulfide Producing Enzyme Cystathionine γ-lyase Contributes to Maternal Hypertension and Placental Abnormalities in Preeclampsia

Abstract

H ydrogen sulfide (H 2 S), a gaseous signaling molecule, promotes vasodilatation 1 and stimulates angiogenesis in the vasculature.2 H 2 S has anti-inflammatory properties 3 and is also cytoprotective against cellular damage induced by lethal hypoxia or reperfusion injury. 4,5 Cystathionine γ-lyase (CSE) is the principal enzyme responsible for the endogenous production of H 2 S.6 Chronic administration of the CSE inhibitor DL-propargylglycine (PAG) leads to elevated blood pressure and vascular remodeling in the rat, 7 and both CSE and H 2 S levels are reduced in pulmonary hypertensive rats. 8Mice genetically deficient in CSE develop age-dependent hypertension, severe hyperhomocysteinemia, and endothelial dysfunction. 9 Clearly, H 2 S has multiple roles in health and disease, 10,11 but its role in pregnancy-induced hypertension is unknown. Editorial see p 2472 Clinical Perspective on p 2522Preeclampsia is a hypertensive syndrome that affects 4% to 7% of all pregnancies and is a major contributor to maternal and fetal morbidity and mortality worldwide. 12 The exact etiology of preeclampsia is unknown; abnormal placentation 13,14 and imbalance in angiogenic factors 15,16 have been implicated in preeclampsia pathogenesis. Importantly, circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1), the endogenous inhibitor of vascular endothelial growth factor and placental 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 ...

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines

“…Clinically, the rats showed decreased proteinuria, hypertension, and glomerular injury (38). Conversely, decreased levels of the precursor molecules of H 2 S have been found in patients with preeclampsia (37,39,40). Chronic administration of a cystathionine g-lyase inhibitor, DL-propargylglycine, to pregnant mice resulted in elevated mean BP, liver damage, and decreased fetal growth.…”

“…H 2 S is a gas known to have vasodilatory, cytoprotective, and angiogenic properties similar to CO. H 2 S is generated by three enzymes, cystathionine g-lyase, cystathionine b-synthase, and 3-mercaptopyruvate sulfurtransferase, using the substrates cystathionine, homocysteine, cysteine, and mercaptopyruvate (36). H 2 S levels have not only been shown to be decreased in preeclampsia, but they seem to modulate levels of sFlt-1 and sEng (29,37). This mechanism may be dependent on VEGF.…”

Maternal Vascular Physiology in Preeclampsia

“…42 Recent studies suggest the involvement of hydrogen sulfide, a gaseous signaling molecule that induces EDH, 43 in preeclampsia-associated vascular dysfunction. Circulating hydrogen sulfide is reduced in pregnant women with preeclampsia, 44 and expression of cystathionine-β-synthase, the enzyme that is involved in desulfuration of l-cysteine into hydrogen sulfide, is attenuated in endothelial cells stimulated with plasma from pregnancies with preeclampsia. 45 Holwerda et al reported that the cystathionine-β-synthase tag single nucleotide polymorphism rs11203172 is associated with a significantly reduced risk to develop early-onset preeclampsia.…”

GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

“…This was correlated with reduced placental growth factor production and increased soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglinin (sEng) release from human umbilical vein endothelial cells which are considered to be markers for the onset of preeclampsia in 155 GYY4137, a Novel Water-Soluble, H 2 S-Releasing Molecule humans. In mice, GYY4137 reversed this effect of PAG treatment, reducing circulating sFlt-1 and sEng levels and restoring fetal growth (Wang et al, 2013).…”