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A Biological role for GnRH I and GnRH II at the maternal-fetal interface Zhou, Junshan

Abstract

Remodeling of the endometrial extracellular matrix, which occurs during the early stages of pregnancy in the human, is mediated by the temporal expression of urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMP) in both the maternal and fetal compartments and counterbalanced by their respective endogenous inhibitors, plasminogen activator inhibitor (PAI-1) and tissue inhibitors of metalloproteinases (TIMPs) in both an autocrine and paracrine manner. To date, the factors capable of regulating the expression of uPA and MMP proteolytic systems at the maternal-fetal interface remain poorly characterized. However, the direct correlation between the expression of Gonadotropin-Releasing Hormone (GnRH I) and the activity of uPA, MMP-2 and MMP-9 in the human endometrium and placenta has led to the hypothesis that GnRH I may play a regulator of this developmental event. In these studies, we have examined the ability of GnRH I and the second mammalian form of GnRH (GnRH II), which is also expressed in the human endometrium and placenta, to regulate uPA/ PAI-1 and MMP-2, MMP-9 /TIMP-1 mRNA and protein expression levels in primary cultures of decidual stromal cells or extravillous cytotrophoblasts isolated from first trimester tissues. GnRH I and GnRH II increased uPA, MMP-2 and MMP-9 mRNA and protein expression levels in both of cell types. In contrast, GnRH I and GnRH JJ were capable of increasing TIMP-1 levels in extravillous cytotrophoblasts but had no significant effect on its expression levels in decidual stromal cell cultures. Furthermore, both forms of GnRH down-regulated PAI-1 mRNA levels in extravillous cytotrophoblasts whereas GnRH I increased and GnRH II decreased PAI-1 mRNA and protein expression levels in these decidual cell cultures. Antagonists specific for the GnRH I receptor, Cetrorelix and Antide, were capable of inhibiting the regulatory effects of GnRH I, but not GnRH II on these primary cell cultures. Collectively, these observations strengthen our hypothesis that GnRH is a key regulator of the proteolytic degradation of the endometrial ECM during implantation. However, the observed biological actions of GnRH I and GnRH II on these primary cell cultures appear to be mediated by distinct, tissue-specific molecular mechanisms, which as yet, remain to be elucidated.

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