Cervical remodeling in term and preterm birth: insights from an animal model.

Proper cervical function is essential for a normal pregnancy and birth to occur. Understanding the mechanisms that take place in normal pregnancy will allow a better comprehension of the complications involved in premature cervical remodeling and lead to better methods of diagnostics and prevention for preterm birth. Unfortunately, human samples are not easily available, and samples that are collected are often confounded by variations in timing and region of cervix from which sample is collected. Animal models, specifically the mouse, have facilitated a great deal of exploration into the mechanisms of cervical function and pathways of preterm birth. This review highlights some of the groundbreaking discoveries that have arisen from murine research including 1) the identification of early pregnancy changes in collagen fibril processing and assembly that result in progressive modifications to collagen architecture with subsequent loss of tissue stiffness during pregnancy, 2) the determination that immune cells are not key to cervical ripening at term but have diverse phenotypes and functions in postpartum repair, and 3) the finding that the process of preterm cervical ripening can differ from term ripening and is dependent on the etiology of prematurity. These findings, which are relevant to human cervical biology, provide new insights that will allow targeted studies on the human cervix as well as identify potential biomarkers for early detection of premature cervical ripening and development of improved therapies to prevent premature ripening of the cervix and subsequent preterm birth.

[1]  P. McMillan,et al.  Macrophage trafficking in the uterus and cervix precedes parturition in the mouse. , 1999, Biology of reproduction.

[2]  I. G. Young,et al.  Uterine eosinophils and reproductive performance in interleukin 5-deficient mice. , 2000, Journal of reproduction and fertility.

[3]  R. Jaenisch,et al.  Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Elovitz,et al.  Animal models of preterm birth , 2004, Trends in Endocrinology & Metabolism.

[5]  R. Muhle,et al.  Intrauterine Bacterial Inoculation Induces Labor in the Mouse by Mechanisms Other than Progesterone Withdrawal1 , 2002, Biology of reproduction.

[6]  Jane E. Norman,et al.  Immunolocalization of Proinflammatory Cytokines in Myometrium, Cervix, and Fetal Membranes During Human Parturition at Term1 , 2002, Biology of reproduction.

[7]  Shannon M. Mitchell,et al.  Dynamic changes in the cervical epithelial tight junction complex and differentiation occur during cervical ripening and parturition. , 2007, Endocrinology.

[8]  R. M. Krisztán,et al.  Morphologic and histochemical evidence for the occurrence of collagenolysis and for the role of , 1980 .

[9]  M. Elovitz,et al.  Preterm and Term Cervical Ripening in CD1 Mice (Mus musculus): Similar or Divergent Molecular Mechanisms?1 , 2009, Biology of reproduction.

[10]  R. Locksley,et al.  Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis , 2011, Science.

[11]  D. Eyre,et al.  Type III collagen: A major constituent of rheumatoid and normal human synovial membrane. , 1975, Connective tissue research.

[12]  E. Ginns,et al.  Mice That Lack Thrombospondin 2 Display Connective Tissue Abnormalities That Are Associated with Disordered Collagen Fibrillogenesis, an Increased Vascular Density, and a Bleeding Diathesis , 1998, The Journal of cell biology.

[13]  Sorin Draghici,et al.  The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: Identification of novel molecular functions involved in this process , 2009, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[14]  G. Bellward,et al.  Serum progesterone levels in the pregnant and postpartum laboratory mouse. , 1974, Endocrinology.

[15]  M. Mahendroo,et al.  Signaling via the type I IL-1 and TNF receptors is necessary for bacterially induced preterm labor in a murine model. , 2006, American journal of obstetrics and gynecology.

[16]  J. McDonald,et al.  Molecular Cloning and Characterization of a Putative Mouse Hyaluronan Synthase* , 1996, The Journal of Biological Chemistry.

[17]  J. Malone Obstetrics and gynecology as a career , 1974 .

[18]  P. Leppert,et al.  Anatomy and Physiology of Cervical Ripening , 1995, Clinical obstetrics and gynecology.

[19]  Gerard Tromp,et al.  The transcriptome of the uterine cervix before and after spontaneous term parturition. , 2006, American journal of obstetrics and gynecology.

[20]  L. Sahlin,et al.  Differential regulation of the progesterone receptor A and B in the human uterine cervix at parturition , 2004, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[21]  P. Bornstein,et al.  Matricellular proteins: extracellular modulators of cell function. , 2002, Current opinion in cell biology.

[22]  B. Zimmermann,et al.  The solubility of collagen of the uterine cervix during pregnancy and labour , 1976, Archiv für Gynäkologie.

[23]  R. Word,et al.  Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. , 2007, Reproduction.

[24]  P. Leppert,et al.  Collagen Changes in Rat Cervix in Pregnancy—Polarized Light Microscopic and Electron Microscopic Studies , 1995, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[25]  K. Hirabayashi,et al.  Reproductive phenotypes in mice with targeted disruption of the 20alpha-hydroxysteroid dehydrogenase gene. , 2007, The Journal of reproduction and development.

[26]  L. Muglia,et al.  Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[27]  S. Robson,et al.  Interleukin‐8 is involved in cervical dilatation but not in prelabour cervical ripening , 2004, Clinical and experimental immunology.

[28]  W. Rath,et al.  Glycosaminoglycans in Cervical Connective Tissue During Pregnancy and Parturition , 1993, Obstetrics and gynecology.

[29]  G. Saade,et al.  Hyaluronidase modifies the biomechanical properties of the rat cervix and shortens the duration of labor independent of myometrial contractility. , 2010, American journal of obstetrics and gynecology.

[30]  D. Russell,et al.  5 alpha-reduced androgens play a key role in murine parturition. , 1996, Molecular endocrinology.

[31]  K. Kwek,et al.  Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. , 2002, The Journal of clinical endocrinology and metabolism.

[32]  R. Romero,et al.  Complement activation triggers metalloproteinases release inducing cervical remodeling and preterm birth in mice. , 2011, The American journal of pathology.

[33]  J. M. Singer,et al.  Use of hyaluronidase for cervical ripening: a randomized trial. , 2007, European journal of obstetrics, gynecology, and reproductive biology.

[34]  Yucel Akgul,et al.  The molecular mechanisms of cervical ripening differ between term and preterm birth. , 2011, Endocrinology.

[35]  D. Russell,et al.  The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. , 1999, Molecular endocrinology.

[36]  Holger Maul,et al.  Cervical light-induced fluorescence in humans decreases throughout gestation and before delivery: Preliminary observations. , 2003, American journal of obstetrics and gynecology.

[37]  B. Sibai,et al.  Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth. , 2001, JAMA.

[38]  Michael House,et al.  Changes in the biochemical constituents and morphologic appearance of the human cervical stroma during pregnancy. , 2009, European journal of obstetrics, gynecology, and reproductive biology.

[39]  S. Andersson,et al.  Estrogen and progesterone metabolism in the cervix during pregnancy and parturition. , 2008, The Journal of clinical endocrinology and metabolism.

[40]  Katherine Luby-Phelps,et al.  Cervical Softening During Pregnancy: Regulated Changes in Collagen Cross-Linking and Composition of Matricellular Proteins in the Mouse1 , 2011, Biology of reproduction.

[41]  Jeff Reese,et al.  Utilization of different aquaporin water channels in the mouse cervix during pregnancy and parturition and in models of preterm and delayed cervical ripening. , 2006, Endocrinology.

[42]  A. Word,et al.  Dynamic changes in cervical glycosaminoglycan composition during normal pregnancy and preterm birth. , 2012, Endocrinology.

[43]  Katherine Luby-Phelps,et al.  Second harmonic generation imaging as a potential tool for staging pregnancy and predicting preterm birth. , 2010, Journal of biomedical optics.

[44]  G. Prestwich,et al.  Regulation of lung injury and repair by Toll-like receptors and hyaluronan , 2005, Nature Medicine.

[45]  Jane E Norman,et al.  Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. , 2003, Molecular human reproduction.

[46]  A. Calder,et al.  The Effects of Mifepristone on Cervical Ripening and Labor Induction in Primigravidae , 1998, Obstetrics and gynecology.

[47]  A. Poole,et al.  Biochemical evidence of collagenase-mediated collagenolysis as a mechanism of cervical dilatation at parturition in the guinea pig. , 1991, Biology of reproduction.

[48]  Asif Ahmed,et al.  Physical and biomechanical characteristics of rat cervical ripening are not consistent with increased collagenase activity. , 2004, American journal of obstetrics and gynecology.

[49]  J. A. Chapman,et al.  Collagen fibril formation. , 1996, The Biochemical journal.

[50]  R. D. Harkness,et al.  Changes in the physical properties of the uterine cervix of the rat during pregnancy , 1959, The Journal of physiology.

[51]  A. Fairhurst,et al.  Temporal Changes in Myeloid Cells in the Cervix during Pregnancy and Parturition1 , 2009, The Journal of Immunology.

[52]  B. Langlois,et al.  Advances in tenascin-C biology , 2011, Cellular and Molecular Life Sciences.

[53]  P. Fields,et al.  The extent to which relaxin promotes proliferation and inhibits apoptosis of cervical epithelial and stromal cells is greatest during late pregnancy in rats. , 2005, Endocrinology.

[54]  M. Elovitz,et al.  Inflammation promotes a cytokine response and disrupts the cervical epithelial barrier: a possible mechanism of premature cervical remodeling and preterm birth. , 2012, American journal of obstetrics and gynecology.

[55]  S. Boslaugh,et al.  Risk for postterm delivery after previous postterm delivery. , 2007, American journal of obstetrics and gynecology.

[56]  P. Bornstein,et al.  Thrombospondin 2 Deficiency in Pregnant Mice Results in Premature Softening of the Uterine Cervix1 , 2004, Biology of reproduction.

[57]  S. Robson,et al.  Macrophages and not granulocytes are involved in cervical ripening. , 2005, Journal of reproductive immunology.

[58]  C. Mendelson,et al.  A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[59]  C. A. de la Motte,et al.  Hyaluronan and its binding proteins during cervical ripening and parturition: dynamic changes in size, distribution and temporal sequence. , 2008, Matrix biology : journal of the International Society for Matrix Biology.

[60]  M. Mahendroo,et al.  Processes Regulating Cervical Ripening Differ From Cervical Dilation and Postpartum Repair: Insights From Gene Expression Studies , 2007, Reproductive Sciences.

[61]  A. Pandya,et al.  Connective tissue and related disorders and preterm birth: clues to genes contributing to prematurity. , 2009, Placenta.

[62]  P. Gallop,et al.  Cross-linking in collagen and elastin. , 1984, Annual review of biochemistry.

[63]  J. Martin Preterm births - United States, 2007. , 2011, MMWR supplements.

[64]  M. Mahendroo,et al.  Timing of Neutrophil Activation and Expression of Proinflammatory Markers Do Not Support a Role for Neutrophils in Cervical Ripening in the Mouse1 , 2006, Biology of reproduction.

[65]  T. Tominaga,et al.  Lysyl oxidase activity in the mouse uterine cervix is physiologically regulated by estrogen. , 1981, Endocrinology.

[66]  G. R. Dodge,et al.  Immunochemical and immunohistochemical evidence of estrogen-mediated collagenolysis as a mechanism of cervical dilatation in the guinea pig at parturition. , 1991, Endocrinology.

[67]  B. Mitchell,et al.  Messenger RNA for progesterone receptor isoforms in the late-gestation rat uterus. , 2002, American journal of physiology. Endocrinology and metabolism.

[68]  L. Junqueira,et al.  Morphologic and histochemical evidence for the occurrence of collagenolysis and for the role of neutrophilic polymorphonuclear leukocytes during cervical dilation. , 1980, American journal of obstetrics and gynecology.

[69]  Vincent C Hascall,et al.  Regulation of hyaluronan expression during cervical ripening. , 2004, Glycobiology.

[70]  R. Stern Devising a pathway for hyaluronan catabolism: are we there yet? , 2003, Glycobiology.

[71]  Andrew M. Miller Connective Tissue , 1972, Nature.

[72]  K. Kimata,et al.  Expression Cloning and Molecular Characterization of HAS Protein, a Eukaryotic Hyaluronan Synthase (*) , 1996, The Journal of Biological Chemistry.

[73]  S. Young,et al.  Transgene Insertion on Mouse Chromosome 6 Impairs Function of the Uterine Cervix and Causes Failure of Parturition1 , 2005, Biology of reproduction.

[74]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[75]  Meredith Akins,et al.  Cervical remodeling during pregnancy and parturition , 2010, Trends in Endocrinology & Metabolism.

[76]  E. H. Luque,et al.  Role of relaxin and estrogen in the control of eosinophilic invasion and collagen remodeling in rat cervical tissue at term. , 1998, Biology of reproduction.

[77]  Michael House,et al.  A study of the anisotropy and tension/compression behavior of human cervical tissue. , 2010, Journal of biomechanical engineering.