Journal of Clinical Endocrinology & Metabolism, Vol 80, 2776-2784, Copyright © 1995 by Endocrine Society

ARTICLES

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

B Casslen, J Nordengren, B Gustavsson, M Nilbert and LR Lund
Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden.

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.

This article has been cited by other articles:

				V. Noskova, B. Bottalico, H. Olsson, A. Ehinger, R. Pilka, B. Casslen, and S. R. Hansson Histamine uptake by human endometrial cells expressing the organic cation transporter EMT and the vesicular monoamine transporter-2 Mol. Hum. Reprod., August 1, 2006; 12(8): 483 - 489. [Abstract] [Full Text] [PDF]

				R. Pilka, V. Noskova, H. Domanski, C. Andersson, S. Hansson, and B. Casslen Endometrial TIMP-4 mRNA is expressed in the stroma, while TIMP-4 protein accumulates in the epithelium and is released to the uterine fluid Mol. Hum. Reprod., August 1, 2006; 12(8): 497 - 503. [Abstract] [Full Text] [PDF]

				H. Emonard, G. Bellon, L. Troeberg, A. Berton, A. Robinet, P. Henriet, E. Marbaix, K. Kirkegaard, L. Patthy, Y. Eeckhout, et al. Low Density Lipoprotein Receptor-related Protein Mediates Endocytic Clearance of Pro-MMP-2{middle dot}TIMP-2 Complex through a Thrombospondin-independent Mechanism J. Biol. Chem., December 24, 2004; 279(52): 54944 - 54951. [Abstract] [Full Text] [PDF]

				J. Nordengren, R. Pilka, V. Noskova, A. Ehinger, H. Domanski, C. Andersson, G. Hoyer-Hansen, S.R. Hansson, and B. Casslen Differential localization and expression of urokinase plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1) mRNA and protein in endometrial tissue during the menstrual cycle Mol. Hum. Reprod., September 1, 2004; 10(9): 655 - 663. [Abstract] [Full Text] [PDF]

				C. Bruse, D. Radu, and A. Bergqvist In situ localization of mRNA for the fibrinolytic factors uPA, PAI-1 and uPAR in endometriotic and endometrial tissue Mol. Hum. Reprod., March 1, 2004; 10(3): 159 - 166. [Abstract] [Full Text] [PDF]

				R. Pilka, C. Whatling, H. Domanski, S. Hansson, P. Eriksson, and B. Casslen Epithelial expression of matrix metalloproteinase-26 is elevated at mid-cycle in the human endometrium Mol. Hum. Reprod., May 1, 2003; 9(5): 271 - 277. [Abstract] [Full Text] [PDF]

				M. Ancelin, H. Buteau-Lozano, G. Meduri, M. Osborne-Pellegrin, S. Sordello, J. Plouet, and M. Perrot-Applanat A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus PNAS, April 30, 2002; 99(9): 6023 - 6028. [Abstract] [Full Text] [PDF]

				T. Sandberg, A. Ehinger, and B. Casslén Paracrine Stimulation of Capillary Endothelial Cell Migration by Endometrial Tissue Involves Epidermal Growth Factor and Is Mediated Via Up-Regulation of the Urokinase Plasminogen Activator Receptor J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1724 - 1730. [Abstract] [Full Text]

				V. Jokimaa, S. Oksjoki, H. Kujari, E. Vuorio, and L. Anttila Expression patterns of cathepsins B, H, K, L and S in the human endometrium Mol. Hum. Reprod., January 1, 2001; 7(1): 73 - 78. [Abstract] [Full Text] [PDF]

				T. Sandberg,, B. Casslén,, B. Gustavsson,, and T. J. Benraad Human Endothelial Cell Migration Is Stimulated by Urokinase Plasminogen Activator:Plasminogen Activator Inhibitor 1 Complex Released from Endometrial Stromal Cells Stimulated with Transforming Growth Factor ß1; Possible Mechanism for Paracrine Stimulation of Endometrial Angiogenesis Biol Reprod, October 1, 1998; 59(4): 759 - 767. [Abstract] [Full Text]

				M. Ancelin, H. Buteau-Lozano, G. Meduri, M. Osborne-Pellegrin, S. Sordello, J. Plouet, and M. Perrot-Applanat A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus PNAS, April 30, 2002; 99(9): 6023 - 6028. [Abstract] [Full Text] [PDF]