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

Progesterone stimulates differentiation and inhibits the growth of end ometrial tissue. Also, progesterone reduces plasminogen activator (PA) activity, which implies reduced turnover of extracellular matrix prot eins in the secretory phase. To elucidate the mechanism responsible fo r reduced PA activity, primary cultures of human endometrial stromal c ells were stimulated with estradiol and progesterone. Conditioned medi a were assayed for urokinase-type and tissue-type PA (u-PA and t-PA, r espectively), PA inhibitor-1 (PAI-1), and PA activity. Binding of [I-1 25]u-pA and [(125)]u-PA:PAI-1 complex to the u-PA receptor and clearan ce of these ligands were studied. The PA activity of conditioned mediu m decreased after stimulation with progesterone, and this was secondar y to a decrease in u-PA, but not t-PA and an increase in PAI-1. Northe rn blot analysis showed induction of PAI-1 messenger ribonucleic acid, whereas the content of u-PA messenger ribonucleic acid was not influe nced. Furthermore, the number of free u-PA receptor-binding sites was increased by estradiol and progesterone. The stromal cells degraded co mplexed u-PA more efficiently than free u-PA, and degradation of both ligands was inhibited by colchicine, chloroquine, and methylamine. Deg radation was increased after hormone treatment, and this was apparentl y 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 transcriptiona l level, but may result from posttranslational mechanisms, such as dec reased turnover of the receptor. Activation of plasminogen by receptor bound u-PA initiates a cascade of proteolytic events in the extracell ular matrix that is important during tissue proliferation. Our data su ggest that differentiated endometrial stroma in the secretory phase re gulates extracellular proteolysis by increased elimination of u-PA thr ough increased release of PAI-1 and increased u-PA receptor density.