ICAM-1 Is Involved in Uterine Receptivity in Rats.

Abstract

The uterine epithelium undergoes extensive molecular changes during early pregnancy to become receptive to an implanting embryo, and this is tightly regulated by ovarian hormones. Many adhesion molecules are known to reorganize during early pregnancy in order to facilitate embryo adhesion to the apical membrane of uterine epithelial cells and play an important role in uterine receptivity. This study examined the changes in distribution, expression and hormonal control of ICAM-1 in the rat uterus during early pregnancy, in ovariectomised rats, pseudo pregnant rats and cultured preimplantation embryos. The use of ICAM-1 specific vivo-morpholino antisense oligonucleotides was employed to discover the role of ICAM-1 in embryo development and implantation. ICAM-1 was visualized in the rat uterus using indirect immunofluorescence microscopy and was absent in the uterine epithelium on day 1 (pre-receptive) and day 3 of pregnancy. By day 6 (receptive) and day 7 of pregnancy at the time of implantation in the rat, ICAM-1 is present in the uterine epithelium and is localized to the apical region. ICAM-1 then disappears in uterine epithelial cells by day 9 (post receptive) of pregnancy. ICAM-1 thus is likely an important molecule in the adhesion of an implanting embryo to the apical membrane of uterine epithelial cells in rats. ICAM-1 is absent in the uterine epithelium of ovariectomised rats treated with oestrogen alone (non-receptive) and apical in the uterine epithelium of rats treated with progesterone alone, or combined with estrogen (receptive); and was apical in day 6 pseudo pregnant animals. Apical ICAM-1 staining in the uterine epithelium, on day 6 of pregnancy and in ovariectomised rats treated with progesterone and in pseudo pregnant rats always coincides with an increase in ICAM-1 monomeric expression on western blots. Dimeric expression of ICAM-1 did not alter from day 1 to day 6 of pregnancy and corresponds to the ICAM-1 protein found in endothelium. ICAM-1 was however present in endothelial cells of blood vessels found in the endometrial stroma at all stages of pregnancy. This indicates that ICAM-1 in uterine epithelial cells is under progesterone control and that endothelial ICAM-1 is not at all influenced by ovarian hormones. Previous studies have suggested that ICAM-1 might be up regulated by cytokines released by implanting embryos; however the use of pseudo pregnant and ovariectomised rats has shown that this is not the case. ICAM-1 is also present in pre-implantation embryos and may be necessary in facilitating embryo adhesion. Moreover, early day 3 embryos exposed to ICAM-1 vivo-morpholino antisense oligonucleotides fail to develop into blastocysts. In summary ICAM-1 is likely an important molecule in the receptivity of uterine epithelial cells and is under progesterone control. ICAM-1 is also a necessary molecule in embryo development. (platform)