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

• Published in: Reproductive sciences (Thousand Oaks, Calif.) Vol. 22; no. 6; p. 718
• Main Authors: Bolnick, Jay M, Kilburn, Brian A, Bolnick, Alan D, Diamond, Michael P, Singh, Manvinder, Hertz, Michael, Dai, Jing, Armant, D Randall
• Format: Journal Article
• Language: English
• Published: United States 01-06-2015
• Subjects: Apoptosis - drug effects; Cell Line; Cyclic GMP - metabolism; Cytoprotection; Dose-Response Relationship, Drug; Female; Humans; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Oxidative Stress; Phosphodiesterase 5 Inhibitors - pharmacology; Pregnancy; Pregnancy Trimester, First; Second Messenger Systems - drug effects; Sildenafil Citrate - pharmacology; Tissue Culture Techniques; Trophoblasts - drug effects; Trophoblasts - metabolism; Trophoblasts - pathology; apoptosis; cGMP; nitric oxide; sildenafil
• ISSN: 1933-7205
• DOI: 10.1177/1933719114557894

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.