Inhibition of progesterone receptor function results in loss of basic fibroblast growth factor expression and stromal cell proliferation during uterine remodelling in the pregnant rat

Abstract

Recent studies suggest that hormonal control of uterine cell proliferation may be moderated by polypeptide growth factors. It remains to be determined, however, whether growth factors cause or are the consequence of hormone action. Basic fibroblast growth factor (bFGF) has been shown to influence cell proliferation and differentiation of a variety of mesoderm-derived cells. To elucidate the regulatory mechanisms controlling stromal cell proliferation and differentiation required for embryo implantation further, immunohistochemical localization of the progesterone receptor and bFGF have been studied. The cell-specific distribution of these proteins was determined in the rat uterus during early pregnancy and after injection of the progesterone receptor antagonist mifepristone (RU 486) at days 1 and 2 post coitum (p.c.) to block implantation. Cell division was restricted to luminal and glandular epithelial cells in pregnant and RU 486-treated rats at day 3 p.c. At day 4 of pregnancy, cell proliferation switched from the epithelia to the stroma in pregnant rats, but after RU 486 treatment division of stromal cells was inhibited significantly (P < 0.05). Progesterone receptor distribution was altered and bFGF was absent in RU 486-blocked stromal cells. Expression of bFGF in luminal and glandular epithelial cells, however, was insensitive to the effects of progesterone receptor antagonism. bFGF content was stimulated in the luminal epithelium and in decidual cells by the implanting embryo. These results indicate that repression of progesterone receptor function in early pregnancy results in a cell-specific loss of bFGF from stromal cells and inhibition of their proliferation. The results further suggest that the regulation of endometrial cell bFGF content is modulated at the site of implantation by the embryo.

Epidermal Growth Factor and Transforming Growth Factor-α Stimulate the Proliferation of Mouse Uterine Stromal Cells

“…The stromal cells do not proliferate when progesterone receptor antagonists are used to block the receptor function (Cullingford and Pollard, 1988;Rider and Psychoyos, 1994) or when anti-progesterone antibodies are administered during early pregnancy (Rider et al, 1986). Progesterone is essential for the growth of uterine stromal cells.…”

Developmental expression and regulation of basic fibroblast growth factor and vascular endothelial growth factor in rat decidua and in a decidual cell line

“…However, progesterone was not able to alter the mRNA expression of either bFGF or VEGF. Progesterone is essential for stromal cell proliferation (Galassi 1968, Sakamoto et al 1983 and, when progesterone action is blocked using a progesterone receptor antagonist, RU 486, stromal cell bFGF expression is lost, these cells stop dividing, and implantation does not occur (Rider & Psychoyos 1994). Our failure to detect any alteration in the bFGF mRNA expression despite the fact that these cells do possess progesterone receptors is probably due to the fact that the cells are derived from highly differentiated decidual cells and not from the stromal cells.…”

“…Because progesterone is also implicated in regulating the process of angiogenesis and the expression of these angiogenic factors in vivo (Cullinan-Bove & Koos 1993, Koos & Olson 1989, Rider & Psychoyos 1994, we examined the role of progesterone on the mRNA expression of bFGF and VEGF in a decidual cell line. Because decidual cells secrete decidual prolactin (PRL)-like hormones and possess the receptors for PRL (Gu et al 1996) we also investigated the role of PRL in the expression of bFGF and VEGF mRNA.…”

Stimulation of a rat uterine stromal cell line in culture reveals a molecular switch for endocrine-dependent differentiation

“…In the present study, we tested if the activation response to cholera toxin plus IL-11 was enhanced by sex steroids because these hormones control stromal cell proliferation and differentiation (Rider & Psychoyos 1994, Lydon et al 1995, Rider 2002, 2004, Gellersen & Brosens 2003. dPRP promoter activity increased (P<0·05) in cells treated with cholera toxin and IL-11 compared with cells cultured in low-serum medium (Fig.…”

“…At the time of embryo implantation in the rat, there is a switch in cellular proliferation from epithelial to stromal compartments (Rider & Psychoyos 1994). Stromal cells do not divide without progesterone, and implantation in mice lacking the progesterone receptor fails, in part, because the uterine stromal cells cannot undergo differentiation (Lydon et al 1995).…”