Differential regulation of the plasminogen activator inhibitor-1 (PAI-1) gene expression by growth factors and progesterone in human endometrial stromal cells.

Abstract

Plasminogen activator inhibitor-1 (PAI-1) has important regulatory functions in haemostasis, extracellular matrix turn-over and cell adhesion. We studied PAI-1 gene expression in primary cultures of endometrial stromal cells, and found that PAI-1 protein and mRNA were increased both by agents associated with differentiation, i.e. progesterone and transforming growth factor beta1 (TGFbeta1), and by those promoting proliferation, i.e. epidermal growth factor (EGF), TGFalpha and basic fibroblast growth factor (bFGF). In order to further elucidate the mechanism of regulation, we transfected stromal cells with an expression construct containing 804 bp of the PAI-1 promoter fused to a chloramphenicol acetyl transferase (CAT) reporter gene. After stimulation with the polypeptide growth factors TGFbeta1, EGF and bFGF we found increased CAT activity, indicating that these stimulators had initiated interaction with the transfected promoter fragment. On the other hand, stimulation with progesterone did not increase CAT activity, even though these cells were perfectly able to respond with increased secretion of PAI-1 protein. Run off experiments demonstrated that progesterone increased the stability of PAI-1 mRNA in endometrial stromal cells. We conclude that the polypeptide growth factors TGFbeta1, EGF and bFGF increase PAI-1 expression by increasing gene transcription. Progesterone, on the other hand, does not interact with the 804 bp promoter region, but increases the stability of PAI-1 mRNA.