This thesis investigates the origin of spontaneous activity in the uterus. This organ does not show any activity until shortly before delivery, where fast and efficient contractions are generated. The aim of this work is to provide insight into the origin of spontaneous oscillations and into the transition from asynchronous to synchronized activity in the pregnant uterus. One intriguing aspect in the uterus is the absence of any pacemaker cell. The organ is composed of muscular cells, which are excitable, and connective cells, whose behavior is purely passive; None of these cells, taken in isolation, spontaneously oscillates. We develop an hypothesis based on the observed strong increase in the electrical coupling between cells in the last days of pregnancy. The study is based on a mathematical model of excitable cells, coupled to each other on a regular lattice, and to a fluctuating number of passive cells, consistent with the known structure of the uterus. The two parameters of the model, the coupling between excitable cells, and between excitable and passive cells, grow during pregnancy.Using both a model based on measured electrophysiological properties, and a generic model of excitable cell, we demonstrate that spontaneous oscillations can appear when increasing the coupling coefficients, ultimately leading to coherent oscillations over the entire tissue. We study the transition towards a coherent regime, both numerically and semi-analytically, using the simple model of excitable cells. Last, we demonstrate that, the realistic model reproduces irregular action potential propagation patterns as well as the bursting behavior, observed in the in-vitro experiments.

The contractile state of microcirculatory vessels is a major determinant of the blood pressure of the whole systemic circulation. Continuous bi-directional communication exists between the endothelial cells (ECs) and smooth muscle cells (SMCs) that regulates calcium (Ca2+) dynamics in these cells. This study presents theoretical approaches to understand some of the important and currently unresolved microcirculatory phenomena. Agonist induced events at local sites have been shown to spread long distances in the microcirculation. We have developed a multicellular computational model by integrating detailed single EC and SMC models with gap junction and nitric oxide (NO) coupling to understand the mechanisms behind this effect. Simulations suggest that spreading vasodilation mainly occurs through Ca2+ independent passive conduction of hyperpolarization in RMAs. Model predicts a superior role for intercellular diffusion of inositol (1,4,5)-trisphosphate (IP3) than Ca2+ in modulating the spreading response. Endothelial derived signals are initiated even during vasoconstriction of stimulated SMCs by the movement of Ca2+ and/or IP3 into the EC which provide hyperpolarizing feedback to SMCs to counter the ongoing constriction. Myoendothelial projections (MPs) present in the ECs have been recently proposed to play a role in myoendothelial feedback. We have developed two models using compartmental and 2D finite element methods to examine the role of these MPs by adding a sub compartment in the EC to simulate MP with localization of intermediate conductance calcium activated potassium channels (IKCa) and IP3 receptors (IP3R). Both models predicted IP3 mediated high Ca2+ gradients in the MP after SMC stimulation with limited global spread. This Ca2+ transient generated a hyperpolarizing feedback of ~ 2-3mV. Endothelium derived hyperpolarizing factor (EDHF) is the dominant form of endothelial control of SMC constriction in the microcirculation. A number of factors have been proposed for the role of EDHF but no single pathway is agreed upon. We have examined the potential of myoendothelial gap junctions (MEGJs) and potassium (K+) accumulation as EDHF using two models (compartmental and 2D finite element). An extra compartment is added in SMC to simulate micro domains (MD) which have NaKα2 isoform sodium potassium pumps. Simulations predict that MEGJ coupling is much stronger in producing EDHF than alone K+ accumulation. On the contrary, K+ accumulation can alter other important parameters (EC Vm, IKCa current) and inhibit its own release as well as EDHF conduction via MEGJs. The models developed in this study are essential building blocks for future models and provide important insights to the current understanding of myoendothelial feedback and EDHF.

<p>Cardiac arrhythmias triggered by both reentrant and focal sources are closely correlated with regions of tissue characterized by significant structural heterogeneity. Experimental and modeling studies of electrical activity in the heart have shown that local microscopic heterogeneities which average out at the macroscale in healthy tissue play a much more important role in diseased and aging cardiac tissue which have low levels of coupling and abnormal or reduced membrane excitability. However, it is still largely unknown how various combinations of microheterogeneity in the intracellular and interstitial spaces affect wavefront propagation in these critical regimes. </p> <p>This thesis uses biophysically realistic 1-D and 2-D computer models to investigate how heterogeneity in the interstitial and intracellular spaces influence both the initiation of ectopic beats and the escape of multiple ectopic beats from a poorly coupled region of tissue into surrounding well-coupled tissue. An approximate discrete monodomain model that incorporates local heterogeneity in both the interstitial and intracellular spaces was developed to represent the tissue domain. </p> <p>The results showed that increasing the effective interstitial resistivity in poorly coupled fibers alters the distribution of electrical load at the microscale and causes propagation to become more like that observed in continuous fibers. In poorly coupled domains, this nearly continuous state is modulated by cell length and is characterized by decreased gap junction delay, sustained conduction velocity, increased sodium current, reduced maximum upstroke velocity, and increased safety factor. In inhomogeneous fibers with adjacent well-coupled and poorly coupled regions, locally increasing the effective interstitial resistivity in the poorly coupled region reduces the size of the focal source needed to generate an ectopic beat, reduces dispersion of repolarization, and delays the onset of conduction block that is caused by source-load mismatch at the boundary between well-coupled and poorly-coupled regions. In 2-D tissue models, local increases in effective interstitial resistivity as well as microstructural variations in cell arrangement at the boundary between poorly coupled and well-coupled regions of tissue modulate the distribution of maximum sodium current which facilitates the unidirectional escape of focal beats. Variations in the distribution of sodium current as a function of cell length and width lead to directional differences in the response to increased effective interstitial resistivity. Propagation in critical regimes such as the ectopic substrate is very sensitive to source-load interactions and local increases in maximum sodium current caused by microheterogeneity in both intracellular and interstitial structure.</p> / Dissertation

Cette thèse étudie l'origine de l'activité spontanée dans l'utérus. Cet organe n'a aucune activité jusqu'à la délivrance, où les contractions rapides et efficaces sont générés. Le but de ce travail est de fournir un aperçu de l'origine des oscillations spontanées et de la transition de l'activité asynchrone à synchronisé dans l'utérus gravide. Un aspect intéressant de l'utérus est l'absence de pacemaker. L'organe est composé de cellules musculaires, qui sont excitables, et conjonctives, dont le comportement est purement passif, aucune de ces cellules, pris isolément, oscillent spontanément. Nous développons une hypothèse basée sur l'augmentation grande du couplage électrique entre les cellules observée pendant la grossesse. L'étude est basée sur deux modèles des cellules excitables, couplé à l'autre sur un réseau régulier, et un nombre variable de cellules passives, en accord avec la structure connue de l'utérus. Les deux paramètres du modèle, le couplage entre les cellules excitables, et entre les cellules excitables et passive, croissent pendant la grossesse. En utilisant les deux modèles, nous démontrons que les oscillations peuvent apparaître spontanément lorsque l'on augmente les coefficients de couplage, conduisant finalement à des oscillations cohérentes sur l'ensemble du tissu. Nous étudions la transition vers un régime cohérent, à la fois numériquement et semi-analytique, en utilisant le modèle simple des cellules excitables. Enfin, nous montrons que le modèle réaliste reproduit irréguliers modes de la propagation d'action potentiels ainsi que le comportement de bursting, observé dans les expériences in vitro. / This thesis investigates the origin of spontaneous activity in the uterus. This organ does not show any activity until shortly before delivery, where fast and efficient contractions are generated. The aim of this work is to provide insight into the origin of spontaneous oscillations and into the transition from asynchronous to synchronized activity in the pregnant uterus. One intriguing aspect in the uterus is the absence of any pacemaker cell. The organ is composed of muscular cells, which are excitable, and connective cells, whose behavior is purely passive; None of these cells, taken in isolation, spontaneously oscillates. We develop an hypothesis based on the observed strong increase in the electrical coupling between cells in the last days of pregnancy. The study is based on a mathematical model of excitable cells, coupled to each other on a regular lattice, and to a fluctuating number of passive cells, consistent with the known structure of the uterus. The two parameters of the model, the coupling between excitable cells, and between excitable and passive cells, grow during pregnancy.Using both a model based on measured electrophysiological properties, and a generic model of excitable cell, we demonstrate that spontaneous oscillations can appear when increasing the coupling coefficients, ultimately leading to coherent oscillations over the entire tissue. We study the transition towards a coherent regime, both numerically and semi-analytically, using the simple model of excitable cells. Last, we demonstrate that, the realistic model reproduces irregular action potential propagation patterns as well as the bursting behavior, observed in the in-vitro experiments.