Stochastic Model of Endothelial TRPV4 Calcium Sparklets: Effect of Bursting and Cooperativity on EDH

Abstract

We examined the endothelial transient receptor vanilloid 4 (TRPV4) channel’s vasodilatory signaling using mathematical modeling. The model analyzes experimental data by Sonkusare and coworkers on TRPV4-induced endothelial Ca2+ events (sparklets). A previously developed continuum model of an endothelial and a smooth muscle cell coupled through microprojections was extended to account for the activity of a TRPV4 channel cluster. Different stochastic descriptions for the TRPV4 channel flux were examined using finite-state Markov chains. The model also took into consideration recent evidence for the colocalization of intermediate-conductance calcium-activated potassium channels (IKCa) and TRPV4 channels near the microprojections. A single TRPV4 channel opening resulted in a stochastic localized Ca2+ increase in a small region (i.e., few μm2 area) close to the channel. We predict micromolar Ca2+ increases lasting for the open duration of the channel sufficient for the activation of low-affinity endothelial KCa channels. Simulations of a cluster of four TRPV4 channels incorporating burst and cooperative gating kinetics provided quantal Ca2+ increases (i.e., steps of fixed amplitude), similar to the experimentally observed Ca2+ sparklets. These localized Ca2+ events result in endothelium-derived hyperpolarization (and SMC relaxation), with magnitude that depends on event frequency. The gating characteristics (bursting, cooperativity) of the TRPV4 cluster enhance Ca2+ spread and the distance of KCa channel activation. This may amplify the EDH response by the additional recruitment of distant KCa channels.