Alterations in gap junction connexin43/connexin45 ratio mediate a transition from quiescence to excitation in a mathematical model of the myometrium

Abstract

The smooth muscle cells of the uterus contract in unison during delivery. These cells achieve coordinated activity via electrical connections called gap junctions which consist of aggregated connexin proteins such as connexin43 and connexin45. The density of gap junctions governs the excitability of the myometrium (among other factors). An increase in gap junction density occurs immediately prior to parturition. We extend a mathematical model of the myometrium by incorporating the voltage-dependence of gap junctions that has been demonstrated in the experimental literature. Two functional subtypes exist, corresponding to systems with predominantly connexin43 and predominantly connexin45, respectively. Our simulation results indicate that the gap junction protein connexin45 acts as a negative modulator of uterine excitability, and hence, activity. A network with a higher proportion of connexin45 relative to connexin43 is unable to excite every cell. Connexin45 has much more rapid gating kinetics than connexin43 which we show limits the maximum duration of a local burst of activity. We propose that this effect regulates the degree of synchronous excitation attained during a contraction. Our results support the hypothesis that as labour approaches, connexin45 is downregulated to allow action potentials to spread more readily through the myometrium.

Computational physiology of uterine smooth muscle

“…24 This type of communication is essential to the propagation of electrical impulses through excitable tissues such as the myometrium. 25,26…”

“…By altering the composition of gap junctions, the spread of the electrical excitation through the myometrium is modulated. 26 Indeed, numerous changes to the myometrium occur up until delivery, with significant differences being observed in the transcriptomes of gestationally matched myometrial biopsies. 29…”

Biomechanics of the human uterus

“…More recent studies incorporated transport of more ionic currents across the membrane or modification of the Hai and Murphy model for force generation during contraction . Models were also developed to describe the electromechanical performance of the whole myometrial tissue due to action potentials, calcium waves, and recruitment of gap junctions . Most recently, a computational biomechanical model for a gravid uterus was developed that employed versions of the chemo‐electro models described above but coupled them with a realistic uterine anatomy segmented from MRI images and viscoelastic deformation material behavior.…”

Functional and Morphological Development of the Womb Throughout Life

“…To obtain a better insight into the transition from global (if not local) quiescence to global excitability, we 160,161 studied a highly simplified model of the myometrium in which cells were laid out on a rectangular grid, as shown in Figure 15. The red disks represent the myometriocytes and the resistors represent the gap junctions, which mediate an electrotonic coupling between the cells.…”