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VASCULAR BIOLOGY

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 Ca²⁺ concentration ([Ca²⁺]_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 Ca²⁺ dynamics to investigate EC responses to different stimuli and the controversial relationship between [Ca²⁺]_i and V_m. The model contains descriptions for the intracellular balance of major ionic species and the release of Ca²⁺ 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 Ca²⁺ mobilization replicate experiments under control and V_m hyperpolarization blockade conditions. They show that peak [Ca²⁺]_i is governed by store Ca²⁺ release while Ca²⁺ influx (and consequently V_m) impacts more the resting and plateau [Ca²⁺]_i. The V_m sensitivity of rest and plateau [Ca²⁺]_i is dictated by a [Ca²⁺]_i "buffering" system capable of masking the V_m-dependent transmembrane Ca²⁺ influx. The model predicts plasma membrane Ca²⁺-ATPase and Ca²⁺ permeability as main players in this process. The heterogeneous V_m impact on [Ca²⁺]_i may elucidate conflicting reports on how V_m influences EC Ca²⁺. 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 Ca²⁺-ATPase

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