Neovascularization represents an important issue in tissue-engineering applications, since survival of implanted cells strongly relies on sufficient oxygen and nutrient supply. We have recently observed that human bone marrow-derived mesenchymal stem cells (MSCs) support neovessel formation originating from coimplanted endothelial cells (ECs) in vivo, suggesting that MSCs may function as perivascular cells by investing and stabilizing nascent EC-derived neovessels. In this study, we investigated EC-induced mural cell differentiation of MSCs in vitro. For this purpose, endothelial progenitor cells (EPCs) from two different origins, namely adult peripheral blood (pbEPCs) and neonatal cord blood (cbEPCs), or human umbilical vein endothelial cells (HUVECs), were cocultured with human MSCs to analyze the effect on MSC differentiation toward a smooth muscle cell (SMC)/pericyte phenotype. EPCs as well as HUVECs increased alpha-smooth muscle actin expression in MSCs upon cocultivation in a time-dependent manner. This effect was strongly dependent on direct cell-to-cell contact and extracellular signal-regulated kinase (ERK) signaling, but was not mediated by heterotypic gap junction communication. Beyond enhanced SMC marker gene expression in MSCs, EPCs also enhanced the functional characteristics of cocultured MSCs by increasing their ability to attach to EC tubes in vitro. In conclusion, our study has shown that EPCs from adult peripheral blood as well as from cord blood commit cocultivated MSCs toward an SMC/pericyte phenotype in a cell-contact- and ERK-dependent manner.