The basis of cellular heterogeneity in atherosclerosis There are three main determinants of cellular heterogeneity in arteries and atherosclerosis. (i) Cell origin. Arteries have different ontogeny. They originate from the neural crest (carotid and proximal aorta), the proepicardium (coronary arteries) or the mesoderma (rest of the body). Also, macrophages are either resident, or increasingly bone marrow-derived with age. (ii) Cell geography. Cell location imprints cells, either via exposure to different shear stress and other haemodynamic forces, as is the case with ECs, or through cell residence within distinct niches in health and disease. Macrophages have distinct phenotypes in the intima or adventitia or respond to intraplaque events such as haemorrhage or lipid accumulation. (iii) Cell plasticity. EndoMT is characterized by a downregulation of EC-specific gene expression and/or the full disappearance of EC fate marker genes along with the appearance of gene expression programmes associated with other cell types, including fibroblasts, SMCs and macrophages, among others.^8–10 Often such ‘foreign’ gene expression is associated with activation of EC proliferation and migration and loss of the protective quiescent metabolic state as well as of the ability to exert normal EC function, such as a response to blood flow, regulation of permeability, and antioxidant capacity. These changes in EC gene expression show a remarkable degree of plasticity and can be temporary activated shortly after myocardial infarction,¹¹ or turn into a permanent EndoMT.¹² A number of pathologic factors including disturbed flow, oxidative stress, hypoxia, and inflammation (e.g. activation of endothelial TGFβ or IL-beta signalling) can initiate EndMT.^13–16 Pro-atherogenic cues trigger SMC phenotypic modulation and atherosclerotic plaque investment by oligoclonal expansion. Plasticity between different SMC-derived states suggests that SMC phenotypic states might be niche-dependent, transitory, and/or interconvertible. A macrophage-to-mesenchymal transition has also been described.