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 Ca(2+), 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) diffusion and that a localized rather than a global EC Ca(2+) mobilization is more likely following SMC stimulation.