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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

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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.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA

    Jay M. Bolnick MD, Brian A. Kilburn BS, Alan D. Bolnick MD, Manvinder Singh MD, Michael Hertz MD, Jing Dai PhD & D. Randall Armant PhD

  2. Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA

    Michael P. Diamond MD

  3. Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA

    D. Randall Armant PhD

  4. Program in Reproductive and Adult Endocrinology, NICHD, NIH, DHHS, Bethesda, MD, USA

    D. Randall Armant PhD

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  1. Jay M. Bolnick MD
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  2. Brian A. Kilburn BS
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Correspondence to D. Randall Armant PhD.

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Bolnick, J.M., Kilburn, B.A., Bolnick, A.D. et al. 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. Reprod. Sci. 22, 718–724 (2015). https://doi.org/10.1177/1933719114557894

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