Activin A promotes human trophoblast invasion by upregulating integrin β3 via ALK4-SMAD4 signaling
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Updated: Aug 25, 2025

Trophoblast Cell Recovery from Angiogenesis-Tube Formation Assay for Differentiation Marker Expression Analysis
Published on: November 8, 2024
Fengxuan Sun1, Lei Cheng2, Ling Guo1
1Center for Reproductive Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China.
Introduction:
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.
Methods:
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.
Results:
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.
Discussion:
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.
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