The mesenchymal stem cells (MSCs) are able to accumulate at the site of tissue damage. For this reason, they must transmigrate across the endothelium. In this study, we focused on skin-derived MSCs (S-MSCs), because the skin represents a useful stem cell source, and we analysed the VEGF released by S-MSCs, because it is known to promote endothelial cell proliferation and vascular permeability. Moreover, we evaluated the influence of S-MSC-conditioned medium on human aortic endothelial cell intracellular calcium concentration ([Ca(2+)](i)) and nitric oxide (NO) production, given their important role in endothelial permeability modulation. Our results suggest that human S-MSCs may interact with the endothelium via paracrine mechanisms, probably leading to an alteration of the endothelial barrier. Consequently, we could hypothesize that a therapeutic approach based on human skin-derived MSCs may have a positive effect on tissue repair.