Growing evidence supports the hypothesis that endothelial cell-derived microparticles (MPs) might contribute to the pathogenesis of cardiovascular (CV) disease. Endothelial cell-derived MPs play a pivotal role in the regulation of the endogenous repair system, thrombosis, coagulation, inflammation, immunity and metabolic memory phenomenon. There is evidence that the MPs are secreted actively accompanied to other regulatory molecules. All these actively synthetizing and secreting factors include proteins, adhesion and intercellular signal molecules, peptides, lipids, free DNAs, microRNAs, and even microparticles (MPs) are defined as cellular secretome. The proteomic profile of secretome is under tightly control of genetic and epigenetic mechanisms, which may altered a secretion of the proteins involved into MPs’ organization. Finally, this may contribute the modification of MP’s after their secretion and throughout transfer to the target cells. As a result, communicative ability of endothelial cell-derived MPs may sufficiently worse. Subsequently, cross talk between some components of secretome might modulate delivering cargos of MPs and their regenerative and proliferative capabilities via intercellular signaling networks. The aim of the review is to discuss the effect of various components of secretome on MP-dependent effects on endothelium.