Endothelial outgrowth cells (EOCs) derived from blood mononuclear cells can differentiate to an endothelial-like phenotype. There are deficits in understanding of the biology of these cells, particularly detailed characterisation of their Ca2+ signalling mechanisms. In the current study, it was found that human EOCs express two forms of ryanodine receptor (RyR1 and RyR2) Ca2+ release channel in their endoplasmic reticulum. Individual EOCs display heterogeneous Ca2+ responses to physiologically relevant regulators fibrinogen and collagen. Some EOCs showed distinctive, multiphasic Ca2+ responses to fibrinogen consisting of rapid decreases, transient increases then a gradual return to the resting levels. Transient elevations in Ca2+ required both L-type voltage gated calcium channels and RyRs. Decreases in Ca2+ stimulated by fibrinogen depended on plasma membrane Ca2+ ATPase pumps, but did not require thapsigargin-sensitive Ca2+ ATPases. These results indicate that EOCs possess sophisticated Ca2+ signalling mechanisms, capable of generating distinct Ca2+ waveforms in response to different physiologically relevant cues. (C) 2011 Elsevier Inc. All rights reserved.