Stochastic model of endothelial TRPV4 calcium sparklets: effect of bursting and cooperativity on EDH

Biophys J. 2015 Mar 24;108(6):1566-1576. doi: 10.1016/j.bpj.2015.01.034.


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 Ca(2+) 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 Ca(2+) increase in a small region (i.e., few μm(2) area) close to the channel. We predict micromolar Ca(2+) 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 Ca(2+) increases (i.e., steps of fixed amplitude), similar to the experimentally observed Ca(2+) sparklets. These localized Ca(2+) 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 Ca(2+) spread and the distance of KCa channel activation. This may amplify the EDH response by the additional recruitment of distant KCa channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Computer Simulation
  • Endothelial Cells / metabolism
  • Kinetics
  • Markov Chains
  • Models, Molecular*
  • Potassium Channels, Calcium-Activated / metabolism
  • Stochastic Processes
  • TRPV Cation Channels / metabolism*


  • Potassium Channels, Calcium-Activated
  • TRPV Cation Channels
  • Calcium