Identification of uterine pacemaker regions at the myometrial-placental interface

Coordinated uterine contractions at the end of gestation are essential for delivering viable offspring in mammals. Contractions are initiated by an electrical signal at the plasma membrane of uterine muscle cells, leading to voltage-dependent calcium entry, and subsequent activation of the intracellular contractile machinery. In contrast to other visceral smooth muscles, it is not known where excitation within the uterus is initiated, and no defined pacemaking region has hitherto been identified. Using a combination of multi-electrode array recordings and high-resolution computational reconstruction of the three-dimensional micro-structure of late pregnant rat uterus, we demonstrate that electrical potentials are initiated in distinct structures within the placental bed of individual implantation sites. These previously unidentified structures represent modified smooth muscle bundles that are derived from bridges between the longitudinal and circular layers. Coordinated implantation and encapsulation by invading trophoblast give rise to isolated placental/myometrial interface bundles that directly connect to the overlying longitudinal smooth muscle layer. Furthermore, the numerous bridge structures co-localise with the vascular network located between the longitudinal and circular layers. Taken together, these observations imply that the anatomical structure of the uterus, combined with site-specific implantation, gives rise to emergent patterns of electrical activity that drive effective contractility during parturition. The identification of the pacemaking zones of the uterus has important consequences for the treatment of disorders of parturition such as preterm labor, postpartum hemorrhage and uterine dystocia.