Follistatin dysregulation impaired trophoblast biological functions by GDF11-Smad2/3 axis in preeclampsia placentas

Introduction: Preeclampsia (PE) is one of the main causes of maternal, fetal, and neonatal mortality. So far, the underlying mechanism of this pregnancy-specific syndrome remains unelucidated. The expression of Follistatin (FST) decreased in maternal serum (especially early onset severe PE) and placental trophoblasts of PE patients. However, whether FST-deficiency in preeclamptic placentas alters trophoblast function remains to be determined. Methods: Trophoblast cell lines were cultured in vitro and LV3 short hairpin RNA (shRNA) was used to silence FST. Growth and differentiation factor 11 (GDF11) expression level in placentas and serum were detected by immunohistochemistry and enzyme-linked immune-sorbent assay, respectively. To verify the effect of reduced FST expression on trophoblasts, microRNA-24-3p, which was predicted to target the 3'-untranslated region (3'-UTR) of FST, was screened out, and miR-24-3p mimic, inhibitor was used to regulate FST expression in trophoblasts. Results: Downregulation of FST significantly enhanced the apoptosis and impaired migration and invasion of trophoblast. Reduced FST caused the upregulation of GDF11 in trophoblasts. Interestingly, GDF11 reduced in preeclamptic placental microvascular endothelial cells. Dysregulation of FST-GDF11-Smad2/3 signaling pathway, leading to increased apoptosis of trophoblast. Expression levels of miR-24-3p, was significantly elevated in preeclamptic placentas. Trophoblast cells transfected with miR-24-3p mimics displayed impaired migration and invasion and increased apoptosis. Treated by miR-24-3p inhibitor, trophoblast cells exhibited rescued function. Discussion: FST-deficiency impaired trophoblast function by upregulating GDF11 levels in trophoblasts. The regulation of FST-GDF11-Smad2/3 axis by microRNAs mimic or inhibitor may be critical to trophoblast function regulation and helps to deepen our understanding of the molecular mechanism of PE.

Automated summary

This study found that the deficiency of FST impairs trophoblast function by upregulating the levels of GDF11, leading to the development of preeclampsia. The high expression of miR-24-3p in preeclamptic placentas may be an important factor in this mechanism.