Role of microprojections in myoendothelial feedback – a theoretical study

Key points • Endothelial microprojections (MPs) are cellular extensions of endothelial cells (ECs) that may be involved in regulation of smooth muscle cell (SMC) constriction in blood vessels. • We developed computational models to investigate the role of MPs in generating EC feedback during SMC stimulation. The models account for the geometry of MPs and heterogeneous distribution of membrane channels and receptors in an EC. • Simulations show that SMC stimulation causes calcium release in and around EC MPs that activates hyperpolarizing currents in ECs and moderates SMC constriction. • The results help us better understand the mechanisms that regulate blood flow and pressure. We investigated the role of myoendothelial projections (MPs) in endothelial cell (EC) feedback response to smooth muscle cell (SMC) stimulation using mathematical modelling. A previously developed compartmental EC–SMC model is modified to include MPs as subcellular compartments in the EC. The model is further extended into a 2D continuum model using a finite element method (FEM) approach and electron microscopy images to account for MP geometry. The EC and SMC are coupled via non‐selective myoendothelial gap junctions (MEGJs) which are located on MPs and allow exchange of Ca2+, K+, Na+ and Cl− ions and inositol 1,4,5‐triphosphate (IP3). Models take into consideration recent evidence for co‐localization of intermediate‐conductance calcium‐activated potassium channels (IKCa) and IP3 receptors (IP3Rs) in the MPs. SMC stimulation causes an IP3‐mediated Ca2+ transient in the MPs with limited global spread in the bulk EC. A hyperpolarizing feedback generated by the localized IKCa channels is transmitted to the SMC via MEGJs. MEGJ resistance (Rgj) and the density of IKCa and IP3R in the projection influence the extent of EC response to SMC stimulation. The predicted Ca2+ transients depend also on the volume and geometry of the MP. We conclude that in the myoendothelial feedback response to SMC stimulation, MPs are required to amplify the SMC initiated signal. Simulations suggest that the signal is mediated by IP3 rather than Ca2+ diffusion and that a localized rather than a global EC Ca2+ mobilization is more likely following SMC stimulation.