Progesterone stimulates degradation of urokinase plasminogen activator (u-PA) in endometrial stromal cells by increasing its inhibitor and surface expression of the u-PA receptor.

Abstract

Progesterone stimulates differentiation and inhibits the growth of endometrial tissue. Also, progesterone reduces plasminogen activator (PA) activity, which implies reduced turnover of extracellular matrix proteins in the secretory phase. To elucidate the mechanism responsible for reduced PA activity, primary cultures of human endometrial stromal cells were stimulated with estradiol and progesterone. Conditioned media were assayed for urokinase-type and tissue-type PA (u-PA and t-PA, respectively), PA inhibitor-1 (PAI-1), and PA activity. Binding of [125I]u-PA and [125I]u-PA:PAI-1 complex to the u-PA receptor and clearance of these ligands were studied. The PA activity of conditioned medium decreased after stimulation with progesterone, and this was secondary to a decrease in u-PA, but not t-PA, and an increase in PAI-1. Northern blot analysis showed induction of PAI-1 messenger ribonucleic acid, whereas the content of u-PA messenger ribonucleic acid was not influenced. Furthermore, the number of free u-PA receptor-binding sites was increased by estradiol and progesterone. The stromal cells degraded complexed u-PA more efficiently than free u-PA, and degradation of both ligands was inhibited by colchicine, chloroquine, and methylamine. Degradation was increased after hormone treatment, and this was apparently due to increased ligand binding, because neither ligand affinity nor the relative rate of degradation was increased. Increased expression of u-PA receptor-binding sites was not regulated on the transcriptional level, but may result from posttranslational mechanisms, such as decreased turnover of the receptor. Activation of plasminogen by receptor bound u-PA initiates a cascade of proteolytic events in the extracellular matrix that is important during tissue proliferation. Our data suggest that differentiated endometrial stroma in the secretory phase regulates extracellular proteolysis by increased elimination of u-PA through increased release of PAI-1 and increased u-PA receptor density.

Low Density Lipoprotein Receptor-related Protein Mediates Endocytic Clearance of Pro-MMP-2·TIMP-2 Complex through a Thrombospondin-independent Mechanism

“…Expression of LRP mRNA significantly increases from the proliferative to the secretory phase, when progesterone concentration is the highest (63). This observation could explain why, in human endometrial stromal cells, uPA activity decreases upon stimulation by progesterone (64). Another example is tumor invasion and metastasis, a hallmark of which is extracellular matrix breakdown.…”

A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189regulates angiogenesis and vascular permeability in human uterus

“…V 189 was shown by Western blot and ELISA to be secreted in vitro during the E 2 ϩ P-dependent differentiation of stromal into decidual cells secreting IGFBP-1, as deduced from the analysis of both proteins from the same medium and the use of specific antibodies. In vitro studies on stromal cells also indicate that V 189 is secreted as an uncleaved isoform (28-30-kDa monomer) in response to E 2 ϩ P. This finding correlates with a low level of uPA expression that has been shown to cleave V 189 (17,18), and with the increase in the expression of plasminogen activator inhibitor-1 (PAI-1) in the same cells under the same conditions (38).…”

Leiomyoma Simultaneously Impair Endometrial BMP-2-Mediated Decidualization and Anticoagulant Expression through Secretion of TGF-β3

“…u-PA is a fibrinolytic agent that is expressed by endometrial tissue and has been shown to increase in normal premenstrual and menstrual endometrial tissue (25,26). PAI-1 modulates the activity of u-PA, and higher levels are normally expressed in menstrual phase endometrium (21)(22)(23).…”

“…The endometrial release of plasminogen activator (PA) activity in uterine fluid increases during the proliferative phase to a maximum at midcycle, is low in the secretory phase, and then increases again premenstrually (18 -21). PA inhibitor 1 (PAI-1), a fibrinolytic modulator that binds to urokinase PA (u-PA), increases from the late proliferative phase, through the secretory phase, to a maximum in the menstrual phase (22)(23)(24)(25)(26). This pattern of gene expression contributes to the hemostatic mechanisms that allow normal menstrual blood flow in the normal uterus.…”