A Multiscale Computational Analysis of Myometrial Excitation during Late Pregnancy

Abstract

The control of uterine activity during pregnancy is a complex process that involves regulating myometrial excitability across multiple scales. While numerous studies have investigated various regulatory mechanisms and established the contributions of ion channels and gap junctions, how these mechanisms interact to produce observed changes in uterine activity remains poorly understood. Pivotal to these efforts are computational models that effectively capture gestational changes in excitability across scales. In this study, we propose a multiscale computational modeling framework that can reproduce measured activity at the cellular and tissue scales at a given gestational stage. At the cellular level, we identify key ion currents underlying the observed electrophysiological properties based on a literature review of their regulation and a sensitivity analysis of the Tong 2011 uterine smooth muscle cell activation model. The conductances of these ion currents are then fit to reproduce characteristic resting membrane potentials and burst properties using Bayesian optimization. To extend to the tissue level, we employ an anisotropic monodomain model, parameterized by the resistivity of late pregnancy uterine muscle, to investigate electrical propagation in a two-dimensional section of uterine tissue. We then apply the multiscale model to study myometrial activation in late pregnancy and elucidate the contributions of ion channel and gap junction regulation in transitioning the uterus from a quiescent state to labor. Our resulting model successfully reproduces measured electrophysiological properties at the cellular level and characteristic single-spike and burst-propagation patterns at the tissue level across the three late-pregnant time points analyzed (days 16/17, 18/19, and 20/21) in a murine model. Furthermore, our results suggest that the regulation of the conductances of the voltage-dependent potassium current (IK1), L-type calcium current (ICaL), and sodium current (INa) is most important in determining preterm uterine excitability. The framework established here will promote the development of more gestationally relevant models to better understand labor progression and the factors involved in dysfunctional labor. Author SummaryPregnancy is marked by drastic changes in the electrical and contractile activity of the uterus. As improper regulation of uterine activity is associated with preterm and dysfunctional labor, it is crucial to understand the physiological mechanisms underlying these changes. Currently, the roles of ion channels in determining cellular dynamics, and gap junctions in cell-to-cell coupling, as well as tissue properties, have been well established. However, how their regulation interacts to produce observed changes in cellular and tissue excitability and, in turn, organ-level activity is far less understood. While existing computational models of uterine electrophysiology have provided a greater insight into these processes, these are formulated for a single time point and cannot interrogate their effects over gestation. In response to this need, we develop a framework to generate a computational model of uterine excitation at a given gestational stage. We apply this to investigate the role of ion channels and gap junctions in transitioning the uterus to labor during late pregnancy. We identify three major ion channels and demonstrate agreement with observed action potential and tissue propagation properties at the analyzed time points. We further highlight how our framework can be applied to investigate other stages, including labor and postpartum.