LAUSR

BACKGROUND Decidualization defects in the endometrium have been demonstrated at the time of delivery in women with severe preeclampsia (sPE) and linger for years, suggesting a maternal contribution to the pathogenesis of this condition. Global transcriptional profiling reveals alterations in gene expression, including downregulation of Annexin A2 (ANXA2) in sPE patients with decidualization resistance. OBJECTIVE We investigated the functional role of ANXA2 deficiency during endometrial decidualization and its potential contribution to shallow trophoblast invasion during implantation and subsequent placentation using in vitro and in vivo modeling. STUDY DESIGN ANXA2 gene and protein levels were assessed during in vitro decidualization of human endometrial stromal cells (hESCs) isolated from biopsies collected from women with previous severe preeclampsia (sPE) (n=5) or normal obstetric outcomes (n=5). Next, ANXA2 was inhibited with small interference RNA (siRNA) in control hESC cells isolated from endometrial biopsies (n=15) as an in vitro model to analyze decidualization defects at the morphological level as well as secretion of prolactin (PRL) and insulin-like growth binding protein-1 (IGFPB1). ANXA2-inhibited cells were used to evaluate motility and promotion of embryo invasion. Decidualization and placentation defects of ANXA2 deficiency were confirmed using an ANXA2-null mouse model. RESULTS ANXA2 gene and protein levels were downregulated during in vitro decidualization of hESCs from women with prior sPE compared to control individuals. To assess its role in the endometrial stroma, we inhibited ANXA2 expression and detected decidualization failure as evidenced by impaired morphological transformation, which was associated with altered actin polymerization and low PRL and IGFBP1 secretions. Functionally, in vitro models demonstrated that ANXA2 inhibition failed to support embryo invasion. This finding was corroborated by reduced trophoblast spreading through hESCs, lack of motility of these cells, and reduced trophoblast invasion in the presence of conditioned media from ANXA2-inhibited cells. Extending our discovery to an animal model, we detected that ANXA2-null mice have a functional deficiency in decidualization and placentation that impairs fetal growth as a feature associated with sPE. CONCLUSIONS Together, in vitro and in vivo results suggest that endometrial defects in ANXA2 expression impair decidualization of endometrial stromal cells as well as the uterine microenvironment that promotes embryo implantation and placentation. Our findings highlight the maternal contribution to the pathogenesis of sPE and suggest that evaluation of ANXA2 may provide a novel strategy to assess a woman's risk of developing this pathology and perhaps discover therapeutic interventions to improve decidualization.