Abstract
A greater understanding of the processes that regulate cervical remodeling during pregnancy, parturition, and the postpartum period is required to understand causes of preterm and posterm birth in which abnormal cervical function is the primary culprit. In the current study, gene expression patterns unique to cervical ripening as compared with cervical dilation and/or postpartum repair are identified in a mouse model. Genes differentially regulated from gestation day 15 to late day 18 reveal processes important for cervical ripening. Genes differentially regulated from late day 18 to 2 hours after birth reveal processes that could be important during cervical dilation or the postpartum recovery period. Based on expression patterns, cervical ripening requires a downregulation of collagen assembly genes; increased synthesis of glycosaminoglycans that disrupt the matrix, such as hyaluronan; increased metabolism of progesterone; and changes in epithelial barrier properties. The latter phases of dilation and postpartum recovery are associated with increased assembly of mature collagen, synthesis of matrix proteins that promote a dense connective tissue, activation of inflammatory responses, prostaglandin synthesis, and further changes in epithelial barrier properties and differentiation. Processes/gene expression required for cervical ripening are distinct from those important in latter phases of cervical remodeling and highlight the importance of timing of tissue collection for understanding the molecular mechanisms of cervical ripening.
Similar content being viewed by others
References
Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S. Births: final data for 2004. Natl Vital Stat Rep. 2006;55(1):1–101.
Word RA, Li XH, Hnat M, Carrick K. Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med. 2007; 25(1):69–79.
Leppi TJ A study of the uterine cervix of the mouse. Anat Rec. 1964;150:51–65.
Read CP, Word RA, Ruscheinsky MA, Timmons BC, Mahendroo MS Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. Reproduction. 2007;134:327–340.
Leppert PC Anatomy and physiology of cervical ripening. Clin Obstet Gynecol. 1995;38:267–279.
Mahendroo MS, Porter A, Russell DW, Word RA The parturition defect in steroid 5a-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol. 1999;13(6): 981–992.
Straach KJ, Shelton JM, Richardson JA, Hascall VC, Mahendroo MS Regulation of hyaluronan expression during cervical ripening. Glycobiology. 2005;15(1):55–65.
Timmons BC, Mahendroo MS Timing of neutrophil activation and expression of proinflammatory markers do not support a role for neutrophils in cervical ripening in the mouse. Biol Reprod. 2006;74(2):236–245.
Word RA, Landrum CP, Timmons BC, Young SG, Mahendroo MS Transgene insertion on mouse chromosome 6 impairs function of the uterine cervix and causes failure of parturition. Biol Reprod. 2005;73(5):1046–1056.
Liggins G. Ripening of the cervix. Semin Perinatol. 1978; 2(3):261–271.
Mackler AM, Iezza G, Akin MR, McMillan P, Yellon SM Macrophage trafficking in the uterus and cervix precedes parturition in the mouse. Biol Reprod. 1999;61(4):879–883.
Sennstrom MB, Ekman G, Westergren-Thorsson G, et al. Human cervical ripening, an inflammatory process mediated by cytokines. Mol Human Reprod. 2000;6(4):375–381.
Thomson AJ, Telfer JF, Young A, et al. Leukocytes infiltrate the myometrium during human parturition: further evidence that labour is an inflammatory process. Hum Reprod. 1999;14(1):229–236.
Sakamoto Y, Moran P, Searle RF, Bulmer JN, Robson SC Interleukin-8 is involved in cervical dilatation but not in prelabour cervical ripening. Clin Exp Immunol. 2004;138(1): 151–157.
Sakamoto Y, Moran P, Bulmer JN, Searle RF, Robson SC Macrophages and not granulocytes are involved in cervical ripening. J Reprod Immunol. 2005;66(2):161–173.
Buhimschi IA, Dussably L, Buhimschi CS, Ahmed A, Weiner CP Physical and biomechanical characteristics of rat cervical ripening are not consistent with increased collagenase activity. Am J Obstet Gynecol. 2004;191(5):1695–1704.
Rimmer D. The effect of pregnancy on the collagen of the uterine cervix of the mouse. J Endocr. 1973;57:413–418.
Osman I, Young A, Ledingham MA, et al. Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Mol Hum Reprod. 2003;9(1):41–45.
Mahendroo M, Cala K, Russell D. 5a-reduced androgens play a key role in murine parturition. Mol Endocrinol. 1996; 10: 380–392.
Timmons BC, Mitchell SM, Gilpin C, Mahendroo MS Dynamic changes in the cervical epithelial tight junction complex and differentiation occur during cervical ripening and parturition. Endocrinology. 2007;148(3):1278–1287.
Drewes PG, Yanagisawa H, Starcher B, et al. Pelvic organ prolapse in fibulin-5 knockout mice: pregnancy-induced changes in elastic fiber homeostasis in mouse vagina. Am J Pathol. 2007;170(2):578–589.
Ozasa H, Tominaga T, Nishimura T, Takeda T. Lysyl oxidase activity in the mouse uterine cervix is physiologically regulated by estrogen. Endocrinology. 1981;109(2):618–621.
van der Slot AJ, Zuurmond AM, Bardoel AF, et al. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem. 2003;278(42): 40967–40972.
Ali S, Robertson H, Wain JH, Isaacs JD, Malik G, Kirby JA A non-glycosaminoglycan-binding variant of CC chemokine ligand 7 (monocyte chemoattractant protein-3) antagonizes chemokine-mediated inflammation. J Immunol. 2005;175(2): 1257–1266.
Havelock JC, Keller P, Muleba N, et al. Human myometrial gene expression before and during parturition. Biol Reprod. 2005;72(3):707–719.
Walz A, Burgener R, Car B, Baggiolini M, Kunkel SL, Strieter RM Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8. J Exp Med. 1991;174(6):1355–1362.
Hassan SS, Romero R, Haddad R, et al.The transcriptome of the uterine cervix before and after spontaneous term parturition. Am J Obstet Gynecol. 2006; 195(3):778–786.
Lin F, Fukuoka Y, Spicer A, et al. Tissue distribution of products of the mouse decay-accelerating factor (DAF) genes: exploitation of a Daf1 knock-out mouse and site-specific monoclonal antibodies. Immunology. 2001;104(2):215–225.
Wiley SR, Cassiano L, Lofton T, et al. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity. 2001;15(5):837–846.
Bornstein P, Agah A, Kyriakides TR The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol. 2004;36(6):1115–1125.
Ge G, Zhang Y, Steiglitz BM, Greenspan DS Mammalian tolloid-like 1 binds procollagen C-proteinase enhancer protein 1 and differs from bone morphogenetic protein 1 in the functional roles of homologous protein domains. J Biol Chem. 2006;281(16):10786–10798.
Jones PL, Jones FS Tenascin-C in development and disease: gene regulation and cell function. Matrix Biol. 2000;19(7): 581–596.
Meijboom LJ, Drenthen W, Pieper PG, et al. Obstetric complications in Marfan syndrome. Int J Cardiol. 2006;110(1):53–59.
Stracke JO, Hutton M, Stewart M, et al. Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19: evidence for a role as a potent basement membrane degrading enzyme. J Biol Chem. 2000;275(20):14809–14816.
Chen HY, Yu SL, Chen CH, et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med. 2007;356(1):11–20.
LaFleur AM, Lukacs NW, Kunkel SL, Matsukawa A. Role of CC chemokine CCL6/C10 as a monocyte chemoattractant in a murine acute peritonitis. Mediators Inflamm. 2004;13(5–6): 349–355.
Kokenyesi R, Armstrong LC, Agah A, Artal R, Bornstein P. Thrombospondin 2 deficiency in pregnant mice results in premature softening of the uterine cervix. Biol Reprod. 2004;70(2):385–390.
Wight T. Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol. 2002;14:617–623.
Russell DL, Doyle KM, Ochsner SA, Sandy JD, Richards JS Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation. J Biol Chem. 2003;278(43):42330–42339.
Kruithof EK, Baker MS, Bunn CL Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood. 1995;86(11):4007–4024.
Yu H, Maurer F, Medcalf RL Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation. Blood. 2002;99(8):2810–2818.
Makino S, Zaragoza DB, Mitchell BF, Robertson S, Olson DM Prostaglandin F2alpha and its receptor as activators of human decidua. Semin Reprod Med. 2007;25(1):60–68.
Stracke JO, Fosang AJ, Last K, et al. Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP). FEBS Lett. 2000;478(1–2):52–56.
Kim DD, Song WC Membrane complement regulatory proteins. Clin Immunol. 2006;118(2–3):127–136.
Drzewiecki G, Tozzi C, Yu Y, Leppert PC A dual mechanism of biomechanical change in rat cervix in gestation and postpartum: applied vascular mechanics. Cardiovas Eng. 2007;5(4): 187–193.
Kitamura K, Ito A, Mori Y, Hirakawa S. Changes in the human uterine cervical collagenase with special reference to cervical ripening. Biochem Med. 1979;22(3):332–338.
Osmers R, Rath W, Adelmann-Grill BC, Fittkow C, Severenyi M, Kuhn W. Collagenase activity in the cervix of non-pregnant and pregnant women. Arch Gynecol Obstet. 1990; 248:75–80.
Rajabi MR, Solomom S, Poole AR Biochemical evidence of collagenase-mediated collagenolysis as a mechanism of cervical dilatation at parturition in the guinea pig. Biol Reprod. 1991;45:764–772.
Sato T, Ito A, Mori Y, Yamashita K, Hayakawa T, Nagase H. Hormonal regulation of collagenolysis in uterine cervical fibroblasts: modulation of synthesis of procollagenase, prostromelysin and tissue inhibitor of metalloproteinases (TIMP) by progesterone and oestradiol-17 beta. Biochem J. 1991; 275(pt 3):645–650.
Huber A, Hudelist G, Czerwenka K, Husslein P, Kubista E, Singer CF Gene expression profiling of cervical tissue during physiological cervical effacement. Obstet Gynecol. 2005; 105(1):91–98.
Osmers R, Rath W, Pflanz MA, Kuhn W, Stuhlsatz HW, Szeverenyi M. Glycosaminoglycans in cervical connective tissue during pregnancy and parturition. Obstet Gynecol. 1993; 81:88–92.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work is supported by National Institutes of Health grant R01 HD043154 (to MM).
Rights and permissions
About this article
Cite this article
Timmons, B.C., Mahendroo, M. Processes Regulating Cervical Ripening Differ From Cervical Dilation and Postpartum Repair: Insights From Gene Expression Studies. Reprod. Sci. 14 (Suppl 8), 53–62 (2007). https://doi.org/10.1177/1933719107309587
Published:
Issue Date:
DOI: https://doi.org/10.1177/1933719107309587