Abstract
Previous in vitro studies have suggested that calreticulin (CALR), which is responsible for the folding and quality control of glycoproteins, may be associated with decidualization. However, its precise role in regulating decidualization has not been explored in vivo. Here, we used pregnant rat models to examine endometrial CALR expression during the peri-implantation period. We also examined whether polypectomy, a procedure that could ameliorate infertility, alters the endometrial expression levels of CALR and several implantation factors in women diagnosed as infertile. In rats, uterine CALR was expressed at a high level at the implantation site, and a marked increase in CALR expression was observed in decidual cells of normal pregnancy. In addition, endometrial CALR expression was enhanced by either administration of estradiol-17β in the delayed implantation rat model or the artificial induction of decidualization in the pseudopregnant rat. In cultured stromal cells, siRNA-mediated silencing of CALR inhibited the decidual stimulus-induced expression of prolactin, decidual/trophoblast prolactin-related protein, and connexin 43. In humans, the endometrial expression levels of the mRNAs encoding CALR and the implantation-related factor insulin-like growth factor binding protein (IGFBP)-7 tended to increase after polypectomy. The strongest positive correlation between expression levels before polypectomy was observed for IGFBP-7 and CALR, and the strength of this correlation increased after the surgery. Thus, endometrial CALR may play a role in the formation of decidua, and the polypectomy of infertile patients may result in the co-operative expression of endometrial factors, including CALR, that could enhance endometrial receptivity.
Highlights
Uterine endometrial stromal cells (ESCs) differentiate into decidual cells during the late secretory phase of the menstrual cycle to prepare for implantation [1]
To determine whether polypectomy influences the expression of implantation-related factors, we examined the effects of excision on the expression levels of Cx43, the insulin-like growth factor binding protein 1 (IGFBP1), IGFBP7, PTGS2, and CALR
There has been little evidence showing the specific expression of CALR in human decidual tissues, but we have demonstrated previously that the knockdown of CALR inhibits the decidualization of cultured human ESCs [4]
Summary
Uterine endometrial stromal cells (ESCs) differentiate into decidual cells during the late secretory phase of the menstrual cycle to prepare for implantation [1]. Previous reports have demonstrated that the regulation of calreticulin (CALR) by a cAMP mediator, named an exchange protein, through direct activation by cAMP-2 (EPAC2) may be involved in the decidualization of human ESCs [4,5]. Previous studies have shown that CALR is expressed in the uterus of primates, including humans [11], and mice [12], and further still, this chaperon may mediate maturation of the endometrial glandular and luminal epithelium, leading to the up-regulation of the leukemia inhibitory factor (LIF) and prostaglandin G/H synthase 2 (PTGS2/COX2), both of which are related to endometrial receptivity [13]. The expression levels of endometrial CALR and other implantation-related factors were compared in the endometrium of infertile patients before and after polypectomy
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