Transforming Growth Factor-β (TGFβ) Receptors I/II Differentially Regulate TGFβ1 and IGF-Binding Protein-3 Mitogenic Effects in the Human Placenta

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 TGFβ receptors (TβR). We have examined IGFBP-3 regulation of IGF-dependent and -independent cytotrophoblast proliferation in first-trimester placental explants and the role of TβRII 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 TGFβ signaling molecules [TGFβ receptor I (TβRI), TβRII, TβRV, Smad-2, and ERK] are expressed in syncytium and/or cytotrophoblast. TGFβ1 (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 TGFβ1 and IGFBP-3 was attenuated by a TβRII function-blocking antibody and by small interfering RNA-mediated knockdown of TβRII (P < 0.05); this was accompanied by a reduction in Smad-2 activation. This study demonstrates that both TGFβ1 and IGFBP-3 signal through TβRI/II to influence human cytotrophoblast proliferation. However, downstream pathways are distinct, because IGFBP-3 acts only through Smad-2, whereas TGFβ1 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.