Arterial media calcification and arterial stiffness are independent predictors of cardiovascular mortality. Both processes reinforce one another, creating a vicious cycle in which transdifferentiation of endothelial cells and vascular smooth muscle cells play a central role. Physiological functioning of vascular smooth muscle cells in the arterial medial layer greatly depends on normal endothelial cell behavior. Endothelial or intimal layer cells are the primary sensors of pathological triggers circulating in the blood during, for example, ageing or inflammation, and often can be seen as initiators of this vicious cycle. As such, the search for treatment of arterial media calcification, which until now has been mainly concentrated at the level of the vascular smooth cell, may need to be expanded to intimal layer targets.