title: A mathematical model of plasma membrane electrophysiology and calcium dynamics in vascular endothelial cells.
abstract: 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.
authors: Dept. of Biomedical Engineering, Florida International University, 10555 W. Flagler St., TEC 2674, Miami, FL 33174, USA.
authors: Haroldo S
authors: HS
authors: Silva
authors: Adam
authors: A
authors: Kapela
authors: Nikolaos M
authors: NM
authors: Tsoukias
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D048429:Cell Size; D018118:Chloride Channels / Q000378:metabolism; D003198:Computer Simulation; D004594:Electrophysiology / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007473:Ion Channels / Q000819:agonists / Q000378:metabolism*; D008564:Membrane Potentials; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008643:Mesentery / Q000098:blood supply*; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D051381:Rats; D015203:Reproducibility of Results; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D007473:Ion Channels; D049990:Membrane Transport Modulators; D024681:Potassium Channels, Calcium-Activated; D015222:Sodium Channels; D050994:Voltage-Dependent Anion Channels; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D011188:Potassium