The role of gap junctions in the excitability of the myometrial smooth muscle network

Doctoral thesis English OPEN
Sheldon, Rachel E.
  • Subject: QR | RG

Dysfunction of the myometrium is a major contributor to preterm labour. The current limitations to effective management of preterm labour is in large part due to our, as yet, incomplete insight into the mechanisms that underlie uterine excitability. The uterus goes through a period of activation towards the end of pregnancy during which the myometrium develops the ability to deliver the baby. Gap junctions are among the most important molecular entities involved in this activation process.\ud \ud In this thesis, a mathematical model based on FitzHugh-Nagumo dynamics is used to study the role that gap junctions play in controlling the excitability of the myometrium. Spatial heterogeneity is introduced into the network through stochastic assignment of coupling strengths based on physiological statistics. It is demonstrated that heterogeneity amplifies the ability of a locally applied stimulus to generate global activity and that the ability of the stimulus to excite the network is strongly dependent on the local spatial correlation structure of the couplings. In networks driven by a pacemaker cell, large coupling strengths preclude activity by reducing the frequency of the stimulating oscillations.\ud \ud The model is extended to incorporate voltage-dependent gap junctions. It is established in the literature that gap-junctional conductance is dependent on the transjunctional voltage of neighbouring myocytes. Two conductance relationships have been observed corresponding to gap junctions composed of connexin-43 or connexin-45 proteins. It is demonstrated here that networks with only connexin-45 proteins are unable to exhibit global excitability whereas networks with connexin-43 proteins always display full activity. The mathematical models are supported by analysis of human and rat RNA expression data which shows that connexin-45 is down-regulated at term. It is hypothesised that connexin-45 blocks activity in the uterus throughout gestation, and is down-regulated at term to allow the uterus to deliver the powerful contractions associated with labour.
  • References (129)
    129 references, page 1 of 13

    Liu, Y., Gold, E. B., Lasley, B. L., and Johnson, W. O. 2004. Factors a↵ecting menstrual cycle characteristics. American Journal of Epidemiology, 160(2), 131-140.

    Lodge, S. and Sproat, J. E. 1981. Resting membrane potentials of pacemaker and non pacemaker areas in rat uterus. Life Sciences, 28, 2251-2256.

    Logothetis, D. E., Jin, T., Lupyan, D., and Rosenhouse-Dantsker, A. 2007. Phosphoinositidemediated gating of inwardly rectifying K+ channels. Pflu¨gers Archiv - European Journal of Physiology, 455, 83-95.

    Lu¨king Jayes, F. C., Britt, J. H., and Esbenshade, K. L. 1997. Role of gonadotropin-releasing hormone pulse frequency in di↵erential regulation of gonadotropins in the gilt. Biology of Reproduction, 56, 1012-1019.

    Lye, S. J., Ou, C-W., Teoh, T-G., Erb, G., Stevens, Y., Casper, R., Patel, F. A., and Challis, J. R. G. 1998. The molecular basis of labour and tocolysis. Fetal and Maternal Medicine Review, 10(3), 121-136.

    Macdonald, S. and Magill-Cuerden, J. (eds). 2011. Mayes' Midwifery. 14th edn. Philadelphia: Bailli`ere Tindall.

    Maeda, K. 2013. Uterine contractions in normal labor developed by a positive feed-back and oscillation. Journal of Health & Medical Informatics, 4(3), 130.

    Magann, E. F., Evans, S., Chauhan, S. P., Lanneau, G., Fisk, A. D., and Morrison, J. C. 2005. The length of the third stage of labor and the risk of postpartum hemorrhage. Obstetrics & Gynecology, 105(2), 290-293.

    Marbaix, E., Kokorine, I., and Henriet, P. 1995. The expression of interstitial collagenase in human endometrium is controlled by progesterone and by oestradiol and is related to menstruation. Biochemical Journal, 305, 1027-1030.

    Marbaix, E., Kokorine, I., Moulin, P., Donnez, J., Eeckhout, Y., and Courtoy, P. J. 1996. Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases. Proceedings of the National Academy of Sciences USA, 93, 9120-9125.

  • Similar Research Results (1)
  • Metrics
    No metrics available
Share - Bookmark