Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3′,5′-cyclic monophosphate signaling

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objective To determine the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on trophoblast invasiveness. Design Laboratory investigation. Setting Academic medical center. Patient(s) Placental tissues discarded after first-trimester terminations were obtained from patients with informed consent. Intervention(s) A cell line, HTR-8/SVneo, established from first-trimester cytotrophoblast, and villous explants, was treated with or without sildenafil, guanosine 3′,5′-cyclic monophosphate (cGMP) analog, cGMP inhibitor, or L-NAME (NG-nitro-L-arginine methyl ester hydrochloride) and cultured on fibronectin or Matrigel. Integrins α6β4 and α1β1 were detected by immunocytochemistry. Main Outcome Measure(s) Trophoblast outgrowth from villous tips, cytotrophoblast cell invasion, and integrin immunostaining were assessed in cytotrophoblast and explant cultures. Result(s) Integrin expression in trophoblast cells ex vivo switched from α6 to α1, and invasiveness increased, when exposed to sildenafil or cGMP agonist. Either cGMP antagonist or L-NAME blocked integrin switching and invasion induced by sildenafil. Elevation of nitric oxide pharmacologically induced invasion, but not when cGMP antagonist was present. Conclusion(s) Sildenafil altered trophoblast phenotype through a process dependent on nitric oxide availability and cGMP accumulation. In addition to its vasoactivity, sildenafil directly stimulates trophoblast extravillous differentiation, which would be favorable for implantation and reduce risk for adverse pregnancy outcomes.

Original languageEnglish (US)
Pages (from-to)1587-1595.e2
JournalFertility and Sterility
Volume103
Issue number6
DOIs
StatePublished - Jan 1 2015

Fingerprint

Guanosine
Trophoblasts
Nitric Oxide
Integrins
NG-Nitroarginine Methyl Ester
First Pregnancy Trimester
Phosphodiesterase 5 Inhibitors
Sildenafil Citrate
Pregnancy Outcome
Informed Consent
Fibronectins
Immunohistochemistry
Outcome Assessment (Health Care)
Phenotype
Cell Line

Keywords

  • Trophoblast invasion
  • guanosine 3′,5′-cyclic monophosphate
  • integrins
  • nitric oxide
  • phosphodiesterase-5 inhibitor

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Reproductive Medicine
  • Medicine(all)

Cite this

Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3′,5′-cyclic monophosphate signaling. / Bolnick, Jay M.; Kilburn, Brian A.; Bolnick, Alan D.; Diamond, Michael Peter; Singh, Manvinder; Hertz, Michael; Dai, Jing; Armant, D. Randall.

In: Fertility and Sterility, Vol. 103, No. 6, 01.01.2015, p. 1587-1595.e2.

Research output: Contribution to journalArticle

Bolnick, Jay M. ; Kilburn, Brian A. ; Bolnick, Alan D. ; Diamond, Michael Peter ; Singh, Manvinder ; Hertz, Michael ; Dai, Jing ; Armant, D. Randall. / Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3′,5′-cyclic monophosphate signaling. In: Fertility and Sterility. 2015 ; Vol. 103, No. 6. pp. 1587-1595.e2.
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AU - Bolnick, Jay M.

AU - Kilburn, Brian A.

AU - Bolnick, Alan D.

AU - Diamond, Michael Peter

AU - Singh, Manvinder

AU - Hertz, Michael

AU - Dai, Jing

AU - Armant, D. Randall

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N2 - Objective To determine the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on trophoblast invasiveness. Design Laboratory investigation. Setting Academic medical center. Patient(s) Placental tissues discarded after first-trimester terminations were obtained from patients with informed consent. Intervention(s) A cell line, HTR-8/SVneo, established from first-trimester cytotrophoblast, and villous explants, was treated with or without sildenafil, guanosine 3′,5′-cyclic monophosphate (cGMP) analog, cGMP inhibitor, or L-NAME (NG-nitro-L-arginine methyl ester hydrochloride) and cultured on fibronectin or Matrigel. Integrins α6β4 and α1β1 were detected by immunocytochemistry. Main Outcome Measure(s) Trophoblast outgrowth from villous tips, cytotrophoblast cell invasion, and integrin immunostaining were assessed in cytotrophoblast and explant cultures. Result(s) Integrin expression in trophoblast cells ex vivo switched from α6 to α1, and invasiveness increased, when exposed to sildenafil or cGMP agonist. Either cGMP antagonist or L-NAME blocked integrin switching and invasion induced by sildenafil. Elevation of nitric oxide pharmacologically induced invasion, but not when cGMP antagonist was present. Conclusion(s) Sildenafil altered trophoblast phenotype through a process dependent on nitric oxide availability and cGMP accumulation. In addition to its vasoactivity, sildenafil directly stimulates trophoblast extravillous differentiation, which would be favorable for implantation and reduce risk for adverse pregnancy outcomes.

AB - Objective To determine the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on trophoblast invasiveness. Design Laboratory investigation. Setting Academic medical center. Patient(s) Placental tissues discarded after first-trimester terminations were obtained from patients with informed consent. Intervention(s) A cell line, HTR-8/SVneo, established from first-trimester cytotrophoblast, and villous explants, was treated with or without sildenafil, guanosine 3′,5′-cyclic monophosphate (cGMP) analog, cGMP inhibitor, or L-NAME (NG-nitro-L-arginine methyl ester hydrochloride) and cultured on fibronectin or Matrigel. Integrins α6β4 and α1β1 were detected by immunocytochemistry. Main Outcome Measure(s) Trophoblast outgrowth from villous tips, cytotrophoblast cell invasion, and integrin immunostaining were assessed in cytotrophoblast and explant cultures. Result(s) Integrin expression in trophoblast cells ex vivo switched from α6 to α1, and invasiveness increased, when exposed to sildenafil or cGMP agonist. Either cGMP antagonist or L-NAME blocked integrin switching and invasion induced by sildenafil. Elevation of nitric oxide pharmacologically induced invasion, but not when cGMP antagonist was present. Conclusion(s) Sildenafil altered trophoblast phenotype through a process dependent on nitric oxide availability and cGMP accumulation. In addition to its vasoactivity, sildenafil directly stimulates trophoblast extravillous differentiation, which would be favorable for implantation and reduce risk for adverse pregnancy outcomes.

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KW - nitric oxide

KW - phosphodiesterase-5 inhibitor

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