(24,31,32,65,73). In addition, EC K Ca channel inhibition can greatly affect arterial vasomotion (53), suggesting an important role of EC electrophysiology in this phenomenon.Isolated ECs can be classified into two subtypes according to their resting V m , namely, K-type and Cl-type (56). K-type EC resting V m levels fall between Ϫ70 and Ϫ60 mV, which is close to the Nernst potential of K ϩ (E K ) and thus indicates a dominant K ϩ membrane conductance, mainly due to the inward rectifier K ϩ (Kir) channel. On the other hand, Cl-type EC potential at rest is usually between Ϫ40 and Ϫ10 mV, which is close to the Nernst potential for Cl Ϫ (E Cl ) and suggests a Cl Ϫ conductance dominance under resting conditions. Experiments on isolated vessels suggest that ECs under hypoosmotic stress (which activates volume-sensitive Cl Ϫ conductance and brings V m toward E Cl ) will not be able to hyperpolarize in response to raised extracellular The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. However, ECs regulate Ca 2ϩ entry and V m by expressing an abundant and diverse collection of plasmalemmal ion channels (55), which are for the most part absent in previous EC models. In addition, considering the balance of the other major intracellular ionic species (i.e., Na ϩ , K ϩ , and Cl Ϫ ) is essential to modeling both single cell V m behavior and cell-to-cell electrochemical coupling as Nernst potentials are concentration gradient dependent and gap junctions are nonselective, allowing the passage of small cytoplasmic ions. Consequently, there is a need to build on previous EC modeling work to provide a more biophysically detailed model of EC plasma membrane electrophysiology and further analyze the extent to which, if any, V m affects EC intracellular Ca 2ϩ dynamics. In the last four decades, mathematical modeling of biological systems has contributed to the basic understanding of physiological behavior. For some organs (i.e., the heart), multiscale models have been developed that describe function at the macroscale level while incorporating mechanisms and events at the subcellular and molecular levels. A similar theoretical progress has not been paralleled in the vasculature. This mathematical model presents a first step toward this direction. The aims of this study were 1) to deliver a mathematical model that captures experimentally observed behavior of vascular ECs (and particularly ECs from rat mesenteric arterioles) and 2) to analyze how these cell responses emerge from the nonlinear interactions of individual cellular components.
METHODSThe present EC model can be divided into two components (Fig. 1). The first component represents the equivalent electrical circuit model of the EC plasma membrane (Membrane Electrophysiology), describing its electrophysiology (Fig. 1A) Figure 1B also shows the IP3-sensitive Ca 2ϩ store, which accounts for Ca 2ϩ releas...