Share This Article:

Expression and localization of prostaglandin receptors and stromal factors in human cervix—Variations in pregnant and non-pregnant states

Abstract Full-Text HTML Download Download as PDF (Size:2185KB) PP. 147-157
DOI: 10.4236/ojmip.2013.34020    3,201 Downloads   6,092 Views   Citations

ABSTRACT

Prostaglandins (PGs) mediate cervical ripening leading to parturition. PGs are used successfully to induce cervical ripening. However, the cell type specific expression of PG receptor subtypes and various stromal factors important for cervical ripening in human cervix is not known. Our objective was to investigate the expression and localization of PG receptors EP1-4 and FP and localization of stromal factors CTGF (connective tissue growth factor), furin, calgranulin  B, ALOX12 (arachidonate 12-lipooxy-genase) and ALOX15 in human cervical tissue from pregnant and non-pregnant women. Cervical biopsies were obtained from non-pregnant (NP), term pregnant (TP) and post-partum (PP) women. The mRNA expression was determined with real-time PCR, protein expression and localization with immunohistochemistry. Our results show that the EP2 mRNA level was higher in the PP group as compared to TP, whereas the EP4 mRNA level was lower in the TP group as compared to NP. Concomitantly stromal EP2 and epithelial EP3 immunoreactivity was higher in the TP as compared to the NP group, while the EP4 immunostaining in glands was lower in the TP as compared to the PP group. Immunostaining of endothelial CTGF, smooth muscle furin and ALOX12, were all lower in the TP group as compared to NP, for CTGF also the PP group was lower than NP. Endothelial calgranulin B

immunoreactivity was higher in the PP group than the NP group. PG receptors and stromal factors exhibit differential expression in the cervix from women in non-pregnant and pregnant states, implying their involvement in the process of cervical ripening.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

S. Blesson, C. , Roos, N. , Stephansson, O. , Masironi, B. , Reinert, S. , Vladic Stjernholm, Y. , Ekman-Ordeberg, G. and Sahlin, L. (2013) Expression and localization of prostaglandin receptors and stromal factors in human cervix—Variations in pregnant and non-pregnant states. Open Journal of Molecular and Integrative Physiology, 3, 147-157. doi: 10.4236/ojmip.2013.34020.

References

[1] Hertelendy, F. and Zakar, T. (2004) Prostaglandins and the myometrium and cervix. Prostaglandins, Leukotrie- nes and Essential Fatty Acids, 70, 207-222.
http://dx.doi.org/10.1016/j.plefa.2003.04.009
[2] Osman, I., Young, A., Ledingham, M.A., Thomson, A.J., Jordan, F., Greer, I.A. and Norman, J.E. (2003) Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Molecular Human Reproduction, 9, 41-45.
http://dx.doi.org/10.1093/molehr/gag001
[3] Sennstrom, M.B., Ekman, G., Westergren-Thorsson, G., Malmstrom, A., Bystrom, B., Endresen, U., Mlambo, N., Norman, M., Stabi, B. and Brauner, A. (2000) Human cervical ripening, an inflammatory process mediated by cytokines. Molecular Human Reproduction, 6, 375-381.
http://dx.doi.org/10.1093/molehr/6.4.375
[4] Ekman, G., Malmstrom, A., Uldbjerg, N. and Ulmsten, U. (1986) Cervical collagen: An important regulator of cervical function in term labor. Obstetrics and Gynecology, 67, 633-636.
http://dx.doi.org/10.1097/00006250-198605000-00006
[5] Bygdeman, M., Bremme, K., Christensen, N., Lundstrom, V. and Green, K. (1980) A comparison of two stable prostaglandin E analogues for termination of early pregnancy and for cervical dilatation. Contraception, 22, 471-483.
http://dx.doi.org/10.1016/0010-7824(80)90100-6
[6] Woodward, D.F., Jones, R.L. and Narumiya, S. (2011) International union of basic and clinical pharmacology. LXXXIII: Classification of prostanoid receptors, updating 15 years of progress. Pharmacological Reviews, 63, 471-538. http://dx.doi.org/10.1124/pr.110.003517
[7] Breyer, R.M., Bagdassarian, C.K., Myers, S.A. and Breyer, M.D. (2001) Prostanoid receptors: Subtypes and signaling. Annual Reviews of Pharmacology and Toxicology, 41, 661-690.
http://dx.doi.org/10.1146/annurev.pharmtox.41.1.661
[8] Gu, G., Gao, Q., Yuan, X., Huang, L. and Ge, L. (2012) Immunolocalization of adipocytes and prostaglandin E2 and its four receptor proteins EP1, EP2, EP3, and EP4 in the caprine cervix during spontaneous term labor. Biology of Reproduction, 86, 1-10.
http://dx.doi.org/10.1095/biolreprod.111.096040
[9] Yellon, S.M., Ebner, C.A. and Sugimoto, Y. (2008) Parturition and recruitment of macrophages in cervix of mice lacking the prostaglandin F receptor. Biology of Reproduction, 78, 438-444.
http://dx.doi.org/10.1095/biolreprod.107.063404
[10] Schmitz, T., Levine, B.A. and Nathanielsz, P.W. (2006) Localization and steroid regulation of prostaglandin E2 receptor protein expression in ovine cervix. Reproduction, 131, 743-750. http://dx.doi.org/10.1530/rep.1.00767
[11] Hassan, S.S., Romero, R., Tarca, A.L., Nhan-Chang, C.L., Vaisbuch, E., Erez, O., Mittal, P., Kusanovic, J.P., Mazaki-Tovi, S., Yeo, L., et al. (2009) The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: Identification of novel molecular functions involved in this process. The Journal of Maternal-Fetal &Neonatal Medicine, 22, 1183-1193.
http://dx.doi.org/10.3109/14767050903353216
[12] Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. and Tessier, P.A. (2003) Proinflammatory activities of S100: Proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. Journal of Immunology, 170, 3233-3242.
[13] Greenlee, K.J., Corry, D.B., Engler, D.A., Matsunami, R.K., Tessier, P., Cook, R.G., Werb, Z. and Kheradmand, F. (2006) Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation. Journal of Immunology, 177, 7312-7321.
[14] Havelock, J.C., Keller, P., Muleba, N., Mayhew, B.A., Casey, B.M., Rainey, W.E. and Word, R.A. (2005) Human myometrial gene expression before and during parturition. Biology of Reproduction, 72, 707-719.
http://dx.doi.org/10.1095/biolreprod.104.032979
[15] Verma, R.P. and Hansch, C. (2007) Matrix metalloproteinases (MMPs): Chemical-biological functions and (Q) SARs. Bioorganic Medicinal Chemistry, 15, 2223-2268.
http://dx.doi.org/10.1016/j.bmc.2007.01.011
[16] Uderhardt, S. and Kronke, G. (2012) 12/15-Lipoxygenase during the regulation of inflammation, immunity, and self-tolerance. Journal of Molecular Medicine, 90, 1247-1256. http://dx.doi.org/10.1007/s00109-012-0954-4
[17] Flatman, S., Morgan, A., McDonald-Gibson, R.G., Davey, A., Jonas, G.E. and Slater, T.F. (1988) 12-lipoxygenase activity in human uterine cervix. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 32, 87-94.
http://dx.doi.org/10.1016/0952-3278(88)90101-9
[18] Smith, G.C., Wu, W.X. and Nathanielsz, P.W. (2001) Lipoxygenase gene expression in baboon intrauterine tissues in late pregnancy and parturition. Molecular Human Reproduction, 7, 587-594.
http://dx.doi.org/10.1093/molehr/7.6.587
[19] Lei, Z.M. and Rao, C.V. (1992) The expression of 15-lipoxygenase gene and the presence of functional enzyme in cytoplasm and nuclei of pregnancy human myometria. Endocrinology, 130, 861-870.
http://dx.doi.org/10.1210/en.130.2.861
[20] Wen, Y., Gu, J., Chakrabarti, S.K., Aylor, K., Marshall, J., Takahashi, Y., Yoshimoto, T. and Nadler, J.L. (2007) The role of 12/15-lipoxygenase in the expression of inter- leukin-6 and tumor necrosis factor-alpha in macrophages. Endocrinology, 148, 1313-1322.
http://dx.doi.org/10.1210/en.2006-0665
[21] Stygar, D., Wang, H., Vladic, Y.S., Ekman, G., Eriksson, H. and Sahlin, L. (2002) Increased level of matrix metalloproteinases 2 and 9 in the ripening process of the human cervix. Biology of Reproduction, 67, 889-894.
http://dx.doi.org/10.1095/biolreprod.102.005116
[22] Blesson, C.S., Buttner, E., Masironi, B. and Sahlin, L. (2012) Prostaglandin receptors EP and FP are regulated by estradiol and progesterone in the uterus of ovariectomized rats. Reproductive Biology and Endocrinology, 10, 3. http://dx.doi.org/10.1186/1477-7827-10-3
[23] Altmae, S., Salumets, A., Bjuresten, K., Kallak, T.K., Wanggren, K., Landgren, B.M., Hovatta, O. and Stavreus-Evers, A. (2011) Tissue factor and tissue factor pathway inhibitors TFPI and TFPI2 in human secretory endometrium—Possible link to female infertility. Reproductive Sciences, 18, 666-678.
[24] Catalano, R.D., Wilson, M.R., Boddy, S.C. and Jabbour, H.N. (2011) Comprehensive expression analysis of prostanoid enzymes and receptors in the human endometrium across the menstrual cycle. Molecular Human Reproduction, 17, 182-192.
http://dx.doi.org/10.1093/molehr/gaq094
[25] Stjernholm, Y., Sahlin, L., Akerberg, S., Elinder, A., Eriksson, H.A., Malmstrom, A. and Ekman, G. (1996) Cervical ripening in humans: Potential roles of estrogen, progesterone, and insulin-like growth factor-I. American Journal of Obstetics and Gynecolology, 174, 1065-1071.
http://dx.doi.org/10.1016/S0002-9378(96)70352-6
[26] Stjernholm, Y., Sahlin, L., Malmstrom, A., Barchan, K., Eriksson, H.A. and Ekman, G. (1997) Potential roles for gonadal steroids and insulin-like growth factor I during final cervical ripening. Obstetrics and Gynecology, 90, 375-380.
http://dx.doi.org/10.1016/S0029-7844(97)00245-7
[27] Kershaw-Young, C.M., Khalid, M., McGowan, M.R., Pitsillides, A.A. and Scaramuzzi, R.J. (2009) The mRNA expression of prostaglandin E receptors EP2 and EP4 and the changes in glycosaminoglycans in the sheep cervix during the estrous cycle. Theriogenology, 72, 251-261.
http://dx.doi.org/10.1016/j.theriogenology.2009.02.018
[28] Rath, W., Osmers, R., Adelmann-Grill, B.C., Stuhlsatz, H.W., Szevereny, M. and Kuhn, W. (1993) Biochemical changes in human cervical connective tissue after intracervical application of prostaglandin E2. Prostaglandins, 45, 375-384.
http://dx.doi.org/10.1016/0090-6980(93)90114-M
[29] El Maradny, E., Kanayama, N., Kobayashi, H., Hossain, B., Khatun, S., Liping, S., Kobayashi, T. and Terao, T. (1997) The role of hyaluronic acid as a mediator and regulator of cervical ripening. Human Reproduction, 12, 1080-1088. http://dx.doi.org/10.1093/humrep/12.5.1080
[30] Sennstrom, M.B., Brauner, A., Bystrom, B., Malmstrom, A. and Ekman, G. (2003) Matrix metalloproteinase-8 correlates with the cervical ripening process in humans. Acta Obstetricia et Gynecologica Scandinavica, 82, 904-911.
[31] Lee, J., Banu, S.K., Subbarao, T., Starzinski-Powitz, A. and Arosh, J.A. (2011) Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits invasion of hu- man immortalized endometriotic epithelial and stromal cells through suppression of metalloproteinases. Molecu- lar and Cellular Endocrinology, 332, 306-313.
http://dx.doi.org/10.1016/j.mce.2010.11.022
[32] Sugimoto, Y. and Narumiya, S. (2007) Prostaglandin E receptors. Journal of Biological Chemistry, 282, 11613-11617. http://dx.doi.org/10.1074/jbc.R600038200
[33] Astle, S., Thornton, S. and Slater, D.M. (2005) Identification and localization of prostaglandin E2 receptors in upper and lower segment human myometrium during pregnancy. Molecular Human Reproduction, 11, 279-287.
http://dx.doi.org/10.1093/molehr/gah158
[34] Arulkumaran, S., Kandola, M.K., Hoffman, B., Hanyaloglu, A.C., Johnson, M.R. and Bennett, P.R. (2012) The roles of prostaglandin EP 1 and 3 receptors in the control of human myometrial contractility. Journal of Clinical Endocrinolology and Metababolism, 97, 489-498.
http://dx.doi.org/10.1210/jc.2011-1991
[35] Hinton, A.C., Grigsby, P.L., Pitzer, B.A., Brockman, D.E., Ittenbach, R.F., Hinton, R.B. and Myatt, L. (2010) Hormonal regulation of prostaglandin E2 receptors: Localization and expression in rat cervical tissue. Reproductive Sciences, 17, 136-146.
[36] Rageh, M.A., Moussad, E.E., Wilson, A.K. and Brigstock, D.R. (2001) Steroidal regulation of connective tissue growth factor (CCN2; CTGF) synthesis in the mouse uterus. Molecular Pathology, 54, 338-346.
http://dx.doi.org/10.1136/mp.54.5.338
[37] Cicha, I., Goppelt-Struebe, M., Yilmaz, A., Daniel, W.G. and Garlichs, C.D. (2008) Endothelial dysfunction and monocyte recruitment in cells exposed to non-uniform shear stress. Clinical Hemorheology and Microcirculation, 39, 113-119.
[38] Kannan, S. (2003) Inflammation: A novel mechanism for the transport of extracellular nucleotide-induced arachidonic acid by S100A8/A9 for transcellular metabolism. Cell Biology International, 27, 593-595.
http://dx.doi.org/10.1016/S1065-6995(03)00082-9
[39] Ra, H.J. and Parks, W.C. (2007) Control of matrix metalloproteinase catalytic activity. Matrix Biology: Journal of the International Society for Matrix Biology, 26, 587-596. http://dx.doi.org/10.1016/j.matbio.2007.07.001
[40] Stawowy, P. and Kappert, K. (2011) The molecular boilogy of furin-like proprotein convertases in vascular remodelling. Methods in Molecular Biology, 768, 191-206.
http://dx.doi.org/10.1007/978-1-61779-204-5_9
[41] Urban, D., Lorenz, J., Meyborg, H., Ghosh, S., Kintscher, U., Kaufmann, J., Fleck, E., Kappert, K. and Stawowy, P. (2013) Proprotein convertase furin enhances survival and migration of vascular smooth muscle cells via processing of pro-nerve growth factor. Journal of Biochemistry, 153, 197-207. http://dx.doi.org/10.1093/jb/mvs137
[42] Skrzypczak-Jankun, E., Jankun, J. and Al-Senaidy, A. (2012) Human lipoxygenase: Developments in its structure, function, relevance to diseases and challenges in drug development. Current Medicinal Chemistry, 19, 5122-5127.
http://dx.doi.org/10.2174/092986712803530520
[43] Kim, H.Y., Jeong, D.W., Park, H.S., Lee, T.Y. and Kim, H.S. (2013) Comparison of 12-lipoxygenase expression in vascular smooth muscle cells from old normotensive Wistar-Kyoto rats with spontaneously hypertensive rats. Hypertension Research, 36, 65-73.
http://dx.doi.org/10.1038/hr.2012.119
[44] Weisinger, G., Grafi-Cohen, M., Hirsh, M., Knoll, E., Sharon, O., Many, A., Limor, R. and Stern, N. (2013) 12S-Lipoxygenase is necessary for human vascular smooth muscle cell survival. Experimental Cell Research, 319, 1586-1593. http://dx.doi.org/10.1016/j.yexcr.2013.04.001

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.