Hepatocyte Growth Factor System in the Mouse Uterus: Variation Across the Estrous Cycle and Regulation by 17-Beta-Estradiol and Progesterone1

Abstract

Hepatocyte growth factor (HGF) and its receptor MET have been implicated in uterine development, pregnancy, and endometrial disorders, such as endometriosis and carcinoma. In vitro studies have shown that HGF acts as a mitogen, motogen, and morphogen on endometrial epithelial cells. However, the expression and regulation of HGF and MET in the uteri of different species remain obscure. The present study aimed to investigate the changes of HGF, MET, and HGF activator (HGFA) expression in the uterine endometrium during the estrous cycle in mice and to explore estrogen and progesterone regulation of their expression. MKI67 immunostaining was conducted to examine the association between HGF/MET expression and endometrial cell proliferation. Endometrial epithelial and stromal cells both expressed HGF, HGFA, and MET, but the cell type-specific patterns changed during the cycle. Estrogen and progesterone differentially regulated HGF, MET, and HGFA expression. Progesterone up-regulated their expression in the stroma and down-regulated their expression in the luminal epithelium, whereas 17-beta-estradiol down-regulated their expression in the glandular epithelium. The pattern of HGF/MET overall correlated with that of MKI67. In conclusion, HGF, HGFA, and MET expression in mouse uterus changes during the estrous cycle in a stage-, cell type-, and compartment-specific manner under the influence of estrogen and progesterone. HGF likely plays a role in cyclic endometrial remodeling, such as cell proliferation via autocrine/paracrine mechanisms in mouse uterus.

Progesterone Inhibits Uterine Gland Development in the Neonatal Mouse Uterus1

“…Hgf and Met were found to be expressed by endometrial epithelium and stroma in the adult mouse uterus, and their tissue-specific expression was tightly controlled by steroidal hormones throughout the estrous cycle [52]. Interestingly, P4 stimulated their expression in the stroma, whereas it inhibited their expression in the epithelia [52].…”

Neonatal Estrogen Receptor β Is Important in the Permanent Inhibition of Epithelial Cell Proliferation in the Mouse Uterus

“…Thus, inhibition of neonatal ER␤ function in the uterine epithelium results in the stimulation of cell proliferation accompanied with a decrease of p27 protein in adult mice. In order to identify the target genes of ER␤ in uterine epithelia of neonatal mice and irreversibly affected the genes to adulthood, the mRNA expression of growth factors and the receptors involved in cell proliferation of adult uterine epithelium (42)(43)(44)(45)(46) was examined, however, almost all the expression in the uteri and vaginae of ␤ERKO mice from days 2 and 90 was not different compared with that of WT mice. Only Igf1r expression in the uteri of ␤ERKO mice was higher than that of WT mice at days 2 and 90 (but not significantly), therefore, the increase of Igf1r expression might be involved in permanent stimulation of uterine epithelial cell proliferation induced by ␤ERKO or neonatal ICI treatment.…”

“…Therefore, p27 protein in the uterine epithelium of adult ␤ERKO mice was decreased, especially after treatment of E2. In order to identify the target genes of ER␤ in the uterine epithelia of neonatal and adult mice, the mRNA expression of growth factors and their receptors involved in cell proliferation of adult uterine epithelium (42)(43)(44)(45)(46) was examined ( Figure S1). The expression of growth factors and their receptors in the uteri and vaginae of ␤ERKO mice at days 2 and 90 was similar to that of WT mice, except for a decrease of one of the vascular endothelial growth factor (VEGF) receptor, Flt1, in the uteri of ␤ERKO mice.…”

HGF and c-Met in pathogenesis of endometrial carcinoma

“…HGF and Met expression and function can be regulated by both estrogen and progesterone. Both the protein and mRNA expressions of HGF and Met in mouse uterus were high at proestrus, drastically decreased at estrus, remained low at metestrus, and increased again at diestrus stage, which were regulated by estrogen and progesterone in mice uterus, suggesting that HGF plays a role in cyclic endometrial remodeling by promoting cell proliferation via autocrine/paracrine mechanisms (24).…”

“…In addition to endometrial stromal cells, HGF produced from endometrial stromal cells can promote the proliferation and migration of endometrial epithelial cells (33). The receptors of HGF were found to express in endometrial epithelia (24), especially c-Met (35). The role of endometrial stromal cells in endometrial epithelial cells may contribute to further understanding on the function of endometrial stromal cells in EU via secreting factors such as HGF.…”