title: Reduced cystathionine γ-lyase and increased miR-21 expression are associated with increased vascular resistance in growth-restricted pregnancies: hydrogen sulfide as a placental vasodilator.
abstract: Increased vascular impedance in the fetoplacental circulation is associated with fetal hypoxia and growth restriction. We sought to investigate the role of hydrogen sulfide (H2S) in regulating vasomotor tone in the fetoplacental vasculature. H2S is produced endogenously by catalytic activity of cystathionine β-synthase and cystathionine γ-lyase (CSE). Immunohistochemical analysis localized CSE to smooth muscle cells encircling arteries in stem villi. Immunoreactivity was reduced in placentas from pregnancies with severe early-onset growth-restriction and preeclampsia displaying abnormal umbilical artery Doppler waveforms compared with preeclamptic placentas with normal waveforms and controls. These findings were confirmed at the protein and mRNA levels. MicroRNA-21, which negatively regulates CSE expression, was increased in placentas with abnormal Doppler waveforms. Exposure of villus explants to hypoxia-reoxygenation significantly reduced CSE protein and mRNA and increased microRNA-21 expression. No changes were observed in cystathionine β-synthase expression, immunolocalized principally to the trophoblast, in pathologic placentas or in vitro. Finally, perfusion of normal placentas with an H2S donor, after preconstriction with a thromboxane mimetic, resulted in dose-dependent vasorelaxation. Glibenclamide and N(G)-nitro-l-arginine methyl ester partially blocked the effect, indicating that H2S acts through ATP-sensitive K(+) channels and nitric oxide synthesis. These results demonstrate that H2S is a powerful vasodilator of the placental vasculature and that expression of CSE is reduced in placentas associated with increased vascular resistance.
authors: Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom.
authors: Tereza
authors: T
authors: Cindrova-Davies
authors: Emilio A
authors: EA
authors: Herrera
authors: Youguo
authors: Y
authors: Niu
authors: John
authors: J
authors: Kingdom
authors: Dino A
authors: DA
authors: Giussani
authors: Graham J
authors: GJ
authors: Burton
mesh_terms: D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D000860:Hypoxia / Q000235:genetics / Q000473:pathology; D066298:In Vitro Techniques; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010477:Perfusion; D010920:Placenta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects* / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D014665:Vasodilator Agents; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide