Activin A increases human trophoblast invasion by upregulating integrin β1 through ALK4.

Activin A promotes human trophoblast invasion during the first trimester of pregnancy and is associated with preeclampsia and pregnancy-induced hypertension (PE/PIH) in naturally conceived pregnancies. However, whether integrin β1 mediates activin A-increased trophoblast invasion remains unknown and the evidence is limited regarding the predictive value of activin A for PE/PIH in women receiving in vitro fertilization (IVF) treatment. Here, we studied the role and underlying molecular mechanisms of integrin β1 in activin A-promoted invasion in immortalized (HTR8/SVneo) and primary human extravillous trophoblast (EVT) cells. A nest case-control study was designed to investigate the predictive/diagnostic value of activin A in IVF pregnancies. Results showed that integrin β1 expression increased after activin A treatment and knockdown of integrin β1 significantly decreased both basal and activin A-increased HTR8/SVneo cell invasion. SB431542 (TGF-β type I receptors inhibitor) abolished activin A-induced SMAD2/SMAD3 phosphorylation and integrin β1 overexpression. Activin A-upregulated integrin β1 expression was attenuated after the depletion of ALK4 or SMAD4 in both HTR8/SVneo and primary EVT cells. Furthermore, we found similar first-trimester activin A levels in IVF patients with or without subsequent PE/PIH. These results reveal that integrin β1 mediates activin A-promoted trophoblast invasion through ALK4-activated SMAD2/3-SMAD4 pathway, and the predictive/diagnostic value of first-trimester maternal serum activin A for hypertensive disorders of pregnancy might be different in IVF population.

Zhu S ，Li Z ，Cui L ，Ban Y ，Leung PCK ，Li Y ，Ma J ... -  《-》

Activin A Increases Human Trophoblast Invasion by Inducing SNAIL-Mediated MMP2 Up-Regulation Through ALK4.

Li Y ，Klausen C ，Zhu H ，Leung PC ... -  《-》

Activin A promotes human trophoblast invasion by upregulating integrin β3 via ALK4-SMAD4 signaling.

Activin A has been widely regarded as an important promoter of trophoblast invasion during the first trimester of pregnancy. However, whether integrin β3 is involved in activin A-upregulated trophoblast invasion and the underlying molecular mechanisms remain largely unknown. We utilized immortalized (HTR8/SVneo) and primary human extravillous trophoblast (EVT) cells, as well as first-trimester chorionic villous explants as study models to investigate the function and underlying molecular mechanisms of integrin β3 in activin A-promoted human trophoblast invasion. We found that activin A increased integrin β3 mRNA and protein levels in both HTR8/SVneo and primary EVT cells, and knockdown of integrin β3 significantly decreased basal and activin A-upregulated trophoblast invasion. Moreover, SB431542 (a specific inhibitor of TGF-β type Ι receptor kinase) abolished activin A-upregulated integrin β3 expression and SMAD2/3 phosphorylation. In addition, siRNA-mediated knockdown of ALK4 or SMAD4 both abolished activin A-upregulated integrin β3 expression in HTR8/SVneo cells, while knockdown of ALK4 or SMAD4 attenuated activin A-upregulated integrin β3 expression in primary EVTs. Our findings reveal the mediation role of integrin β3 in activin A-upregulated human trophoblast invasion and that activin An upregulates integrin β3 expression in an ALK4-SMAD4 signaling-dependent manner.

Sun F ，Cheng L ，Guo L ，Su S ，Li Y ，Yan J ... -  《-》

Bone morphogenetic protein 2 promotes human trophoblast cell invasion by upregulating N-cadherin via non-canonical SMAD2/3 signaling.

Zhao HJ ，Klausen C ，Li Y ，Zhu H ，Wang YL ，Leung PCK ... -  《Cell Death & Disease》

Activin A, B, and AB increase human trophoblast cell invasion by up-regulating N-cadherin.

Li Y ，Klausen C ，Cheng JC ，Zhu H ，Leung PC ... -  《-》