Abstract
Embryo implantation into the uterine wall is a highly modulated, complex process. We previously demonstrated that Annexin A1 (AnxA1), which is a protein secreted by epithelial and inflammatory cells in the uterine microenvironment, controls embryo implantation in vivo. Here, we decipher the effects of recombinant AnxA1 in this phenomenon by using human trophoblast cell (BeWo) spheroids and uterine epithelial cells (Ishikawa; IK). AnxA1-treated IK cells demonstrated greater levels of spheroid adherence and upregulation of the tight junction molecules claudin-1 and zona occludens-1, as well as the glycoprotein mucin-1 (Muc-1). The latter effect of AnxA1 was not mediated through IL-6 secreted from IK cells, a known inducer of Muc-1 expression. Rather, these effects of AnxA1 involved activation of the formyl peptide receptors FPR1 and FPR2, as pharmacological blockade of FPR1 or FPR1/FPR2 abrogated such responses. The downstream actions of AnxA1 were mediated through the ERK1/2 phosphorylation pathway and F-actin polymerization in IK cells, as blockade of ERK1/2 phosphorylation reversed AnxA1-induced Muc-1 and claudin-1 expression. Moreover, FPR2 activation by AnxA1 induced vascular endothelial growth factor (VEGF) secretion by IK cells, and the supernatant of AnxA1-treated IK cells evoked angiogenesis in vitro. In conclusion, these data highlight the role of the AnxA1/FPR1/FPR2 pathway in uterine epithelial control of blastocyst implantation.
Highlights
The endometrium is a critical tissue for the establishment and maintenance of pregnancy, during which it undergoes extensive physiological changes and demonstrates extraordinary plasticity.Cyclic changes in its tissues enable the endometrium to convert to a receptive state, allowing implantation, attachment, and invasion by the embryo through the epithelium into the underlying stromal compartment [1,2]
We first confirmed that uterine epithelial cells express and secrete Annexin A1 (AnxA1), and express its receptors, FPR1 and FPR2 (Figure S1)
The concentration-response curves demonstrated that AnxA1, Boc-2, cyclosporine H, and WRW4 did not affect the cellular viability under any of the concentrations employed in our studies following either 24 or 48 h of incubation (Figure S2A,C–E)
Summary
The endometrium is a critical tissue for the establishment and maintenance of pregnancy, during which it undergoes extensive physiological changes and demonstrates extraordinary plasticity. Uterine receptivity is improved when estradiol levels decrease and high levels of progesterone are present [3] Under these specific conditions, glycoproteins are expressed and highly secreted to prepare the endothelium for embryo attachment, tight junctions are reinforced, and angiogenesis occurs [2,7]. These findings suggest that AnxA1 may play a crucial role in the maintenance of the uterine microenvironment, in relation to maintenance of a receptive environment during implantation [27] To further understand this process, in the current study we have elucidated the direct actions of AnxA1 on the initial events of blastocyst implantation in cultured human uterine epithelial cells
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