Bioinformatics, Computational and Systems Biology
Alejandro Perez (he/him/his)
Undergraduate student
Florida International University, Florida, United States
Ahmed Assad
Undergraduate student
Florida International University, Florida, United States
Nikolaos M. Tsoukias
Professor at Department of Biomedical Engineering
Florida International University
Miami, Florida, United States
Vascular endothelial cells (ECs) can sense electrical, chemical, or mechanical stimuli and respond to modulate smooth muscle cell (SMC) contractility. Thus, they play an important role in vascular tone regulation and blood flow control. Central to their vasoactive functions is the regulation of membrane potential (Vm) and of the free cytosolic Ca2+ concentration ([Ca2+]i). Endothelial cells express a variety of ion channels that enable them to tightly regulate Vm and [Ca2+]i and different molecular players allow them to initiate electrical and Ca2+ signals critical for network blood flow coordination. Understanding the complex cellular dynamics is critical for deciphering vascular regulation and tissue perfusion in health and disease. In this study, we present a comprehensive mathematical model of EC electrophysiology and Ca2+ dynamics that matches experimentally observed behavior in cerebral artery ECs. We use this model to elucidate how cell responses emerge from the nonlinear interactions of individual cellular components. The presented model will provide the foundation for the development of multicellular models of the vasculature which can facilitate investigations of cerebral blood flow control in health and the mechanisms resulting in perfusion deficits in brain disorders.
A detailed EC model is adapted to cerebral microcirculation and captures salient features of Ca2+ and Vm dynamics. The proposed model contains some of the most important ion channels identified in cerebral endothelial cells. These include volume-regulated anion channels (VRAC), Ca2+ activated Cl- channels (CaCC), inward rectifier (KIR), small conductance (SKCa), and intermediate conductance Ca2+ activated (IKCa) potassium channels. The model also incorporates different transporter and exchangers such as Na+- K+- 2Cl- cotransporter (NaKCl), Na+-K+-ATPase (NaK), plasma membrane Ca2+-ATPase (PMCA), and Na+/Ca2+ exchanger (NCX). Moreover, the model incorporates non-selective cation channels (NSC), including store-operated channels (Orai1), DAG-activated channels (TRPC1, TRPC3, and TRPC6), and mechanosensitive channels (TRPV4 and Piezo 1). Lastly, the IP3 receptors (IP3Rs) mediate calcium release from intracellular stores and a signaling pathway for G-protein-coupled receptors stimulates the catalysis of PIP2 into IP3 and DAG by phospholipase C (Fig. 1) and increases in shear stress activate mechanosensitive channels. Vm dynamics are captured by a standard Hodgkin-Huxley type formalism and the intracellular concentrations of Ca+, K+, Na+, and Cl- ions are monitored through mass balances.
The detailed model of a cerebral artery EC integrates key molecular players of membrane electrophysiology and calcium dynamics. The model includes the main ion channels identified in this cell type and accounts for intracellular store dynamics. Model parameters quantifying ionic currents are determined from independent experimental data or optimized by fitting integrated cell responses. The model can capture resting Vm and Ca2+ levels and transients following electrical or chemo-mechanical stimulation. The model provides the building block for multicellular model representations of the cerebral microvasculature that will allow us to bridge the gap between cellular-level mechanisms and macroscale-level control of blood perfusion in the brain in health and disease states.