A mathematical model of plasma membrane electrophysiology and calcium dynamics in vascular endothelial cells

Department of Biomedical Engineering, Florida International University, Miami, Florida Submitted 22 October 2006 ; accepted in final form 20 March 2007 Vascular endothelial cells (ECs) modulate smooth muscle cell (SMC) contractility, assisting in vascular tone regulation. Cytosolic Ca 2+ concentration ([Ca 2+ ] i ) and membrane potential ( V m ) play important roles in this process by controlling EC-dependent vasoactive signals and intercellular communication. The present mathematical model integrates plasmalemma electrophysiology and Ca 2+ dynamics to investigate EC responses to different stimuli and the controversial relationship between [Ca 2+ ] i and V m . The model contains descriptions for the intracellular balance of major ionic species and the release of Ca 2+ from intracellular stores. It also expands previous formulations by including more detailed transmembrane current descriptions. The model reproduces V m responses to volume-regulated anion channel (VRAC) blockers and extracellular K + concentration ([K + ] o ) challenges, predicting 1 ) that V m changes upon VRAC blockade are [K + ] o dependent and 2 ) a biphasic response of V m to increasing [K + ] o . Simulations of agonist-induced Ca 2+ mobilization replicate experiments under control and V m hyperpolarization blockade conditions. They show that peak [Ca 2+ ] i is governed by store Ca 2+ release while Ca 2+ influx (and consequently V m ) impacts more the resting and plateau [Ca 2+ ] i . The V m sensitivity of rest and plateau [Ca 2+ ] i is dictated by a [Ca 2+ ] i "buffering" system capable of masking the V m -dependent transmembrane Ca 2+ influx. The model predicts plasma membrane Ca 2+ -ATPase and Ca 2+ permeability as main players in this process. The heterogeneous V m impact on [Ca 2+ ] i may elucidate conflicting reports on how V m influences EC Ca 2+ . The present study forms the basis for the development of multicellular EC-SMC models that can assist in understanding vascular autoregulation in health and disease. microcirculation; vascular tone regulation; calcium influx pathway(s), plasma membrane Ca 2+ -ATPase Address for reprint requests and other correspondence: N. M. Tsoukias, Dept. of Biomedical Engineering, Florida International Univ., 10555 W. Flagler St., TEC 2674, Miami, FL 33174 (e-mail: tsoukias{at}fiu.edu )