Semin Thromb Hemost 2007; 33(1): 111-117
DOI: 10.1055/s-2006-958469
Copyright © 2007 by Thieme Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Role of Decidualization in Regulating Endometrial Hemostasis during the Menstrual Cycle, Gestation, and in Pathological States

Charles J. Lockwood1 , Graciela Krikun1 , Mizanur Rahman1 , Rebeca Caze1 , Lynn Buchwalder1 , Frederick Schatz1
  • 1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
Further Information

Publication History

Publication Date:
23 January 2007 (online)

ABSTRACT

Progesterone-induced decidualized human endometrial stromal cells form a hemostatic envelope that protects against hemorrhage during invasion of endometrial capillaries by implanting blastocyst-derived cytotrophoblasts (CTs). This hemostatic milieu reflects co-upregulated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation and plasminogen activator inhibitor type 1, which inactivates tissue-type plasminogen activator, the primary fibrinolytic agent. During deep invasion of the decidua, CTs breach and remodel spiral arteries and arterioles to produce high-conductance vessels. Shallow invasion results in incomplete vascular transformation and an underperfused fetal-placental unit associated with preeclampsia and intrauterine growth restriction. Decidual hemorrhage and severe thrombophilias elicit aberrant thrombin generation from decidual cell-expressed TF. Such thrombin induces decidual cells to synthesize and secrete soluble fms-like tyrosine kinase-1 (sFlt-1), the matrix metalloproteinases MMP-1 and MMP-3, and the neutrophil chemoattractant interleukin-8. Excess sFlt-1 at the implantation site may inhibit CT invasion by altering the angiogenic factor balance. During abruptions, thrombin-enhanced MMP-1, MMP-3 by decidual cells and neutrophil-derived proteases degrade the decidual and fetal membrane extracellular matrix to promote preterm premature rupture of the membranes. In association with long-term progestin-only contraception, overexpression of decidual cell-derived thrombin promotes aberrant angiogenesis and vessel maintenance to contribute to abnormal uterine bleeding.

REFERENCES

  • 1 Nemerson Y. Tissue factor and hemostasis.  Blood. 1988;  71 1-8
  • 2 Drake T A, Morrissey J H, Edgington T S. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis.  Am J Pathol. 1989;  134 1087-1097
  • 3 Tilley R, Mackman N. Tissue factor in hemostasis and thrombosis.  Semin Thromb Hemost. 2006;  32 5-10
  • 4 Mignatti P, Rifkin D B. Biology and biochemistry of proteinases in tumor invasion.  Physiol Rev. 1993;  73 161-195
  • 5 Tabanelli S, Tang B, Gurpide E. In vitro decidualization of human endometrial stromal cells.  J Steroid Biochem Mol Biol. 1992;  42 337-344
  • 6 Lockwood C J, Nemerson Y, Guller S et al.. Progestational regulation of human endometrial stromal cell tissue factor expression during decidualization.  J Clin Endocrinol Metab. 1993;  76 231-236
  • 7 Lockwood C J, Krikun G, Papp C et al.. The role of progestationally regulated stromal cell tissue factor and type-1 plasminogen activator inhibitor (PAI-1) in endometrial hemostasis and menstruation.  Ann NY Acad Sci. 1994;  734 57-79
  • 8 Lockwood C J, Krikun G, Papp C et al.. Biological mechanisms underlying RU 486 clinical effects: inhibition of endometrial stromal cell tissue factor content.  J Clin Endocrinol Metab. 1994;  79 786-790
  • 9 Schatz F, Aigner S, Papp C et al.. Plasminogen activator activity during decidualization of human endometrial stromal cells is regulated by plasminogen activator inhibitor 1.  J Clin Endocrinol Metab. 1995;  80 2504-2510
  • 10 Irwin J C, Kirk D, King R JB et al.. Hormonal regulation of human endometrial stromal cells in culture: an in vitro model for decidualization.  Fertil Steril. 1989;  52 761-768
  • 11 Schatz F, Krikun G, Caze R et al.. Progestin-regulated expression of tissue factor in decidual cells: implications in endometrial hemostasis, menstruation and angiogenesis.  Steroids. 2003;  68 849-860
  • 12 Mackman N. Regulation of the tissue factor gene.  Thromb Haemost. 1997;  78 747-754
  • 13 Krikun G, Schatz F, Mackman N et al.. Regulation of tissue factor gene expression in human endometrium by transcription factors Sp1 and Sp3.  Mol Endocrinol. 2000;  14 393-400
  • 14 Moore K L. The Developing Human. 4th ed. Philadelphia, PA; W.B. Saunders 1988
  • 15 Oka C, Makino T, Itakura I et al.. Chemical abortion in patients with recurrent fetal loss.  Nippon Sanka Fujinka Gakkai Zasshi. 1991;  43 239-240
  • 16 Ramsey E M, Houston M L, Harris J W. Interactions of the trophoblast and maternal tissues in three closely related primate species.  Am J Obstet Gynecol. 1976;  124 645-647
  • 17 Brosens J J, Pijnenborg R, Brosens I A. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature.  Am J Obstet Gynecol. 2002;  187 1416-1423
  • 18 Edmonds D K, Lindsay K S, Miller J F et al.. Early embryonic mortality in women.  Fertil Steril. 1982;  38 447-453
  • 19 Coughlin S R. Protease-activated receptors in hemostasis, thrombosis and vascular biology.  J Thromb Haemost. 2005;  3 1800-1814
  • 20 Runic R, Schatz F, Wan L et al.. Effects of Norplant on endometrial tissue factor expression and blood vessel structure.  J Clin Endocrinol Metab. 2000;  85 3853-3859
  • 21 Hickey M, Carati F, Manconi B J et al.. The measurement of endometrial perfusion in Norplant users: a pilot study.  Hum Reprod. 2000;  15 1086-1091
  • 22 Krikun G, Critchley H, Schatz F et al.. Abnormal uterine bleeding during progestin-only contraception may result from free radical-induced alterations in angiopoietin expression.  Am J Pathol. 2002;  161 979-986
  • 23 Lockwood C J, Krikun G, Koo A B et al.. Differential effects of thrombin and hypoxia on endometrial stromal and glandular epithelial cell vascular endothelial growth factor expression.  J Clin Endocrinol Metab. 2002;  87 4280-4286
  • 24 Lockwood C J, Kumar P, Krikun G et al.. Effects of thrombin, hypoxia, and steroids on interleukin-8 expression in decidualized human endometrial stromal cells: implications for long-term progestin-only contraceptive-induced bleeding.  J Clin Endocrinol Metab. 2004;  89 1467-1475
  • 25 Ferrara N. Molecular and biological properties of vascular endothelial growth factor.  J Mol Med. 1999;  77 527-543
  • 26 Strieter R M, Kunkel S L, Elner V M. Interleukin-8. A corneal factor that induces neovascularization.  Am J Pathol. 1992;  141 1279-1284
  • 27 Di Paolo S, Volpe P, Grandaliano G et al.. Increased placental expression of tissue factor is associated with abnormal uterine and umbilical Doppler waveforms in severe preeclampsia with fetal growth restriction.  J Nephrol. 2003;  16 650-657
  • 28 Schatz F, Toti P, Arcuri F et al.. Thrombin regulates expression of soluble fms-like tyrosine kinase-1 in first trimester decidual cells: implications for preeclampsia. Paper presented at: 53rd Annual Meeting of the Society for Gynecologic Investigation 2006 (abst 674)
  • 29 Karumanchi S A, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the “chicken-and-egg” question.  Endocrinology. 2004;  145 4835-4837
  • 30 Roberts J M, Gammill H S. Preeclampsia: recent insights.  Hypertension. 2005;  46 1243-1249
  • 31 Lockwood C J, Toti P, Arcuri F et al.. Mechanisms of abruption-induced premature rupture of the fetal membranes: thrombin-enhanced interleukin-8 expression in term decidua.  Am J Pathol. 2005;  167 1443-1449
  • 32 Malak T M, Ockleford C D, Bell S C et al.. Confocal immunofluorescence localization of collagen types I, III, IV, V and VI and their ultrastructural organization in term human fetal membranes.  Placenta. 1993;  14 385-406
  • 33 Maragoudakis M E, Tsopanoglou N E, Andriopoulou P. Mechanism of thrombin-induced angiogenesis.  Biochem Soc Trans. 2002;  30 173-177
  • 34 Rosen T, Schatz F, Kuczynski E et al.. Thrombin-enhanced matrix metalloproteinase-1 expression: a mechanism linking placental abruption with premature rupture of the membranes.  J Matern Fetal Neonatal Med. 2002;  11 11-17
  • 35 Mackenzie A P, Schatz F, Krikun G et al.. Mechanisms of abruption-induced premature rupture of the fetal membranes: thrombin enhanced decidual matrix metalloproteinase-3 (stromelysin-1) expression.  Am J Obstet Gynecol. 2004;  191 1996-2001
  • 36 Birkedal-Hansen H, Moore W G, Bodden M K et al.. Matrix metalloproteinases: a review.  Crit Rev Oral Biol Med. 1993;  4 197-250
  • 37 Baggiolini M. Chemokines and leukocyte traffic.  Nature. 1998;  392 565-568
  • 38 Maymon E, Romero R, Pacora P et al.. Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection.  Am J Obstet Gynecol. 2000;  183 94-99
  • 39 Vu T H, Werb Z. Gelatinase B: structure, regulation, and function. In: Parks WC, Mecham R Matrix Metalloproteinases. San Diego, CA; Academic Press 1998: 115-148
  • 40 Meis P J, Klebanoff M, Thom E et al.. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.  N Engl J Med. 2003;  348 2379-2385

Frederick SchatzPh.D. 

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine

333 Cedar Street, Room 335 FMB, P.O. Box 208063, New Haven, CT 06511

Email: frederick.schatz@yale.edu