Annexin A2 is critical for embryo adhesiveness to the human endometrium by RhoA activation through F-actin regulation.
Annexin A2 (ANXA2) is present in vivo in the mid- and late-secretory endometria and is mainly localized in the luminal epithelium. Our aim was to evaluate its function in regulating the human implantation process. With an in vitro adhesion model, constructed to evaluate how the mouse embryo and JEG-3 spheroids attach to human endometrial epithelial cells, we demonstrated that ANXA2 inhibition significantly diminishes embryo adhesiveness. ANXA2 is also implicated in endometrial epithelial cell migration and trophoblast outgrowth. ANXA2 was seen to be linked to the RhoA/ROCK pathway and to regulate cell adhesion. We noted that ANXA2 inhibition significantly reduces active RhoA, although RhoA inactivation does not alter the ANXA2 levels. RhoA inactivation and ROCK inhibition also moderate embryo adhesiveness to endometrial epithelial cells. We corroborated that the induction of constitutively active RhoA partially reverses the effects of ANXA2 inhibition on endometrial adhesiveness. These molecules colocalize on the plasma membrane of endometrial epithelial cells, and a large proportion of ANXA2 and RhoA are colocalized in the F-actin networks. The functional effects of ANXA2 inhibition and RhoA/ROCK inactivation are associated with significant alterations in F-actin organization and its depolymerization. ANXA2 may act upstream of the RhoA/ROCK pathway by regulating F-actin remodeling and is a key factor in human endometrial adhesiveness.
Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Fundación Investigación Clínico de Valencia Instituto de Investigacion Sanitaria, Valencia, Spain.
Tamara
T
Garrido-Gómez
Francisco
F
Dominguez
Alicia
A
Quiñonero
Carlos
C
Estella
Felipe
F
Vilella
Antonio
A
Pellicer
Carlos
C
Simon
D000199:Actins / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D017306:Annexin A2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D010064:Embryo Implantation; D004717:Endometrium / Q000166:cytology*; D005260:Female; D006801:Humans; D034741:RNA, Small Interfering; D015854:Up-Regulation; D055815:Young Adult; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
C472822:ANXA2 protein, human; D000199:Actins; D017306:Annexin A2; D017931:DNA Primers; D034741:RNA, Small Interfering; D020742:rhoA GTP-Binding Protein