Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3',5'-cyclic monophosphate signaling.
Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3',5'-cyclic monophosphate signaling.
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DOI：
10.1016/j.fertnstert.2015.02.025
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发表时间：
2015-06
影响因子：
6.7
通讯作者：
Armant, D. Randall
中科院分区：
文献类型：
--
作者：
Bolnick, Jay M.;Kilburn, Brian A.;Bolnick, Alan D.;Diamond, Michael P.;Singh, Manvinder;Hertz, Michael;Dai, Jing;Armant, D. Randall
关键词：
确定西地那非（一种 5 型磷酸二酯酶抑制剂）对滋养层侵袭性的影响。实验室调查。学术医疗中心。妊娠早期终止后丢弃的胎盘组织是从知情同意的患者那里获得的。细胞系 HTR-8/SVneo 是由妊娠早期细胞滋养层和绒毛外植体建立的，用或不用西地那非、鸟苷 3',5'-环单磷酸 (cGMP) 类似物、cGMP 抑制剂或 L-NAME（NG-硝基-L-精氨酸甲酯盐酸盐）进行处理，并在纤连蛋白或基质胶上培养。采用免疫细胞化学法检测整合素α6β4和α1β1。在细胞滋养层和外植体培养物中评估绒毛尖端的滋养层生长、细胞滋养层细胞侵袭和整合素免疫染色。当暴露于西地那非或 cGMP 激动剂时，离体滋养层细胞中的整合素表达从 α6 转变为 α1，并且侵袭性增加。 cGMP 拮抗剂或 L-NAME 均可阻断西地那非诱导的整合素转换和侵袭。一氧化氮的升高可通过药物诱导入侵，但当存在 cGMP 拮抗剂时则不会。西地那非通过依赖于一氧化氮可用性和 cGMP 积累的过程改变滋养层表型。除了其血管活性外，西地那非还直接刺激滋养层绒毛外分化，这将有利于着床并降低不良妊娠结局的风险。 （Fertil Steril® 2015；103：1587–95。©2015 美国生殖医学会。）
To determine the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on trophoblast invasiveness. Laboratory investigation. Academic medical center. Placental tissues discarded after first-trimester terminations were obtained from patients with informed consent. 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. Trophoblast outgrowth from villous tips, cytotrophoblast cell invasion, and integrin immunostaining were assessed in cytotrophoblast and explant cultures. 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. 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. (Fertil Steril® 2015;103: 1587–95. ©2015 by American Society for Reproductive Medicine.)
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