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

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.