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

Jay M. Bolnick, Brian A. Kilburn, Alan D. Bolnick, Michael P. Diamond, Manvinder Singh, Michael Hertz, Jing Dai, D. Randall Armant

Research output: Contribution to journalArticle

6 Scopus citations

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-NG-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.

Original languageEnglish (US)
Pages (from-to)718-724
Number of pages7
JournalReproductive Sciences
Volume22
Issue number6
DOIs
StatePublished - Jun 12 2015

Keywords

  • apoptosis
  • cGMP
  • nitric oxide
  • sildenafil

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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