Maternal and Fetal Health Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Research, Fifth Floor, St. Mary's Hospital, Oxford Road, Manchester M13 9WL, United Kingdom.
Endocrinology. 2010 Apr;151(4):1723-31. doi: 10.1210/en.2009-0896. Epub 2010 Feb 19.
Maternal IGFs regulate cytotrophoblast proliferation and, thereby, placental growth and function. IGF bioavailability is controlled by IGF-binding proteins (IGFBPs); in placenta, IGFBP-3 is particularly abundant. In other systems, IGFBP-3 can regulate cellular events independently of IGFs; these effects are thought to be mediated by TGFbeta receptors (TbetaR). We have examined IGFBP-3 regulation of IGF-dependent and -independent cytotrophoblast proliferation in first-trimester placental explants and the role of TbetaRII in mediating these effects. In the presence of IGFBP-3 (50 nm), IGF-induced (10 nm) proliferation (monitored by immunohistochemical analysis of Ki67 expression and bromodeoxyuridine incorporation) was significantly reduced (P < 0.05). IGFBP-3 also reduced basal proliferation independently of IGF receptor signaling. Immunohistochemical analysis demonstrated that TGFbeta signaling molecules [TGFbeta receptor I (TbetaRI), TbetaRII, TbetaRV, Smad-2, and ERK] are expressed in syncytium and/or cytotrophoblast. TGFbeta1 (10 ng/ml) enhanced cytotrophoblast proliferation and activated both Smad-2 and ERK-1/2, whereas IGFBP-3 activated only Smad-2. The function of both TGFbeta1 and IGFBP-3 was attenuated by a TbetaRII function-blocking antibody and by small interfering RNA-mediated knockdown of TbetaRII (P < 0.05); this was accompanied by a reduction in Smad-2 activation. This study demonstrates that both TGFbeta1 and IGFBP-3 signal through TbetaRI/II to influence human cytotrophoblast proliferation. However, downstream pathways are distinct, because IGFBP-3 acts only through Smad-2, whereas TGFbeta1 also phosphorylates ERK, resulting in opposite effects on cytotrophoblast proliferation. The effects of maternal growth signals on placental growth and function therefore depend on the balance of ligands, receptors, and signaling molecules at the syncytiotrophoblast surface. Therapeutic manipulation of this balance might offer a strategy to optimize placental development and pregnancy outcome.
母体 IGF 调节滋养细胞的增殖，从而调节胎盘的生长和功能。IGF 的生物利用度受 IGF 结合蛋白 (IGFBPs) 控制；在胎盘组织中，IGFBP-3 尤为丰富。在其他系统中，IGFBP-3 可独立于 IGF 调节细胞事件；这些作用被认为是由 TGFbeta 受体 (TbetaR) 介导的。我们已经研究了 IGFBP-3 对滋养细胞增殖的影响，包括 IGF 依赖性和非依赖性增殖，并研究了 TbetaRII 在介导这些作用中的作用。在存在 IGFBP-3（50nm）的情况下，IGF（10nm）诱导的增殖（通过 Ki67 表达和溴脱氧尿苷掺入的免疫组织化学分析监测）显著降低（P<0.05）。IGFBP-3 还可独立于 IGF 受体信号降低基础增殖。免疫组织化学分析表明，TGFbeta 信号分子[TGFbeta 受体 I（TbetaRI）、TbetaRII、TbetaRV、Smad-2 和 ERK]在合体滋养层和/或滋养细胞中表达。TGFbeta1（10ng/ml）增强滋养细胞增殖，并激活 Smad-2 和 ERK-1/2，而 IGFBP-3 仅激活 Smad-2。TbetaRII 功能阻断抗体和 TbetaRII 的小干扰 RNA 介导敲低均减弱了 TGFbeta1 和 IGFBP-3 的功能（P<0.05）；同时也降低了 Smad-2 的激活。本研究表明，TGFbeta1 和 IGFBP-3 通过 TbetaRI/II 信号影响人滋养细胞的增殖。然而，下游途径是不同的，因为 IGFBP-3 仅通过 Smad-2 起作用，而 TGFbeta1 还可磷酸化 ERK，从而对滋养细胞增殖产生相反的影响。因此，母体生长信号对胎盘生长和功能的影响取决于合胞滋养层表面配体、受体和信号分子的平衡。对这种平衡的治疗性干预可能为优化胎盘发育和妊娠结局提供一种策略。
