title: Sildenafil Prevents Apoptosis of Human First-Trimester Trophoblast Cells Exposed to Oxidative Stress: Possible Role for Nitric Oxide Activation of 3',5'-cyclic Guanosine Monophosphate Signaling.
abstract: Human first-trimester trophoblast cells proliferate at low O2, but survival is compromised by oxidative stress, leading to uteroplacental insufficiency. The vasoactive drug, sildenafil citrate (Viagra, Sigma, St Louis, Missouri), has proven useful in reducing adverse pregnancy outcomes. An important biological function of this pharmaceutical is its action as an inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 activity, which suggests that it could have beneficial effects on trophoblast survival. To investigate whether sildenafil can prevent trophoblast cell death, human first-trimester villous explants and the HTR-8/SVneo cytotrophoblast cell line were exposed to hypoxia and reoxygenation (H/R) to generate oxidative stress, which induces apoptosis. Apoptosis was optimally inhibited during H/R by 350 ng/mL sildenafil. Sildenafil-mediated survival was reversed by l-N(G)-nitro-l-arginine methyl ester hydrochloride or cGMP antagonist, indicating a dependence on both nitric oxide (NO) and cGMP. Indeed, either a cGMP agonist or an NO generator was cytoprotective independent of sildenafil. These findings suggest a novel intervention route for patients with recurrent pregnancy loss or obstetrical placental disorders.
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Jay M
authors.initials: JM
authors.lastname: Bolnick
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kilburn
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Bolnick
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Diamond
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Manvinder
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hertz
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA Program in Reproductive and Adult Endocrinology, NICHD, NIH, DHHS, Bethesda, MD, USA D.Armant@Wayne.edu.
authors.forename: D Randall
authors.initials: DR
authors.lastname: Armant
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D015290:Second Messenger Systems / Q000187:drug effects*; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D020030:Nitric Oxide Donors; D058986:Phosphodiesterase 5 Inhibitors; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP
keywords: apoptosis; cGMP; nitric oxide; sildenafil