Cardiovascular disease is a global health problem. Atherosclerosis, a chronic, systemic inflammatory disease that involves the walls of the large- and medium-sized elastic arteries and large muscular arteries represents the disease underlying the occurrence of cardiovascular disease. Smooth muscle cells (SMCs), the most abundant cell type in blood vessels wall, play a pivotal role in the pathogenesis of atherosclerosis. During atherogenesis SMCs shift from a differentiated/contractile phenotype toward a dedifferentiated/synthetic state, finally culminating in the formation of the atheromatous plaque. The question remains open as to whether intimal SMCs derive from contractile SMCs through a process of dedifferentiation (the expression of SMC plasticity), or whether they result from a pre-existing SMC subpopulation in the media that is prone to be activated (atheroma-prone phenotype) and to migrate into the intima. In the first part (chapter 1) of this thesis, we describe the epidemiology of cardiovascular disease, as well as the pathogenesis of atherosclerosis and the role of SMCs in atherogenesis. In Chapter 2 of this thesis, we describe our observation that a SMC population harbouring the features of an atheroma-prone phenotype, and characterized by high levels of CaM, can be selectively isolated from the human carotid artery media only when in the presence of macrophage-derived foam cells from plaque. In Chapter 3, we demonstrate that a transition from a contractile to a synthetic SMC phenotype takes place within the media of intracranial aneurysms within, thus suggesting that SMC phenotypic switch is not exclusive to atherosclerotic plaque formation but occurs –and likely plays a role- also in aneurysm formation. In Chapter 4, we investigate the histopathology of extracranial venous wall in multiple sclerosis patients affected by chronic cerebrospinal venous outflow insufficiency. We describe alterations of the vessel lumen that are not accompanied by changes in medial SMC phenotype, but rather by a peculiar organisation of advential collagen fibers. In Chapter 5, we review the current literature supporting the underestimated role of the adventitial myofibroblasts in atherosclerosis and vascular remodeling. Finally (chapter 6), the different topics of my thesis are discussed in a systematic manner.