The role of gap junctions in the excitability of the myometrial smooth muscle network
Sheldon, Rachel E.
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.