Abstract
The spontaneous emergence of contraction-inducing electrical activity in the uterus at the beginning of labor remains poorly understood, partly due to the seemingly contradictory observation that isolated uterine cells are not spontaneously active. It is known, however, that the expression of gap junctions increases dramatically in the approach to parturition, by more than one order of magnitude, which results in a significant increase in inter-cellular electrical coupling. In this paper, we build upon previous studies of the activity of electrically excitable smooth muscle cells (myocytes) and investigate the mechanism through which the coupling of these cells to electrically passive cells results in the generation of spontaneous activity in the uterus. Using a recently developed, realistic model of uterine muscle cell dynamics, we investigate a system consisting of a myocyte coupled to passive cells. We then extend our analysis to a simple two-dimensional lattice model of the tissue, with each myocyte being coupled to its neighbors, as well as to a random number of passive cells. We observe that different dynamical regimes can be observed over a range of gap junction conductances: at low coupling strength, corresponding to values measured long before delivery, the activity is confined to cell clusters, while the activity for high coupling, compatible with values measured shortly before delivery, may spread across the entire tissue. Additionally, we find that the system supports the spontaneous generation of spiral wave activity. Our results are both qualitatively and quantitatively consistent with observations from in vitro experiments. In particular, we demonstrate that the increase in inter-cellular electrical coupling observed experimentally strongly facilitates the appearance of spontaneous action potentials that may eventually lead to parturition.
Highlights
It is well known that the contraction of uterine smooth muscle cells is triggered by electrical activity resulting from action potentials that evolve from single spikes to spike trains in the lead up to parturition [1,2,3]
We investigate the hypothesis mentioned in the introduction, namely that the interaction between coupled myocytes and passive cells is fundamental to their spontaneous activation during the late stages of pregnancy
We investigate the dependence of the myocyte behaviour on the conductance of gap junctions between myocytes and passive cells, Gp, the passive cell resting potential, Vpr, and the average number of passive cells coupled to a myocyte, np
Summary
It is well known that the contraction of uterine smooth muscle cells (myocytes) is triggered by electrical activity resulting from action potentials that evolve from single spikes to spike trains in the lead up to parturition [1,2,3]. The precise mechanism underlying the transition of the uterus from the quiescent organ seen during most stages of pregnancy, to the rhythmically contracting muscle observed at the onset of labor, remains to be fully explained. Preterm births, which occur prior to 37 weeks of gestation, can spontaneously arise from early, undesired uterine contractions [4], and this process is highly significant from a clinical perspective. Preterm births have been implicated as the cause of over a million neonatal deaths per year worldwide, and in around 50% of all cases of infant neurological damage [4]. A clearer understanding of the mechanism of spontaneous uterine tissue contraction could greatly facilitate the development of effective strategies to help curb neonatal mortality and morbidity
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