Hypotheses of vascular injury. (a) In the “inside-out” hypothesis the first target of injury is vascular endothelium, which produces inflammatory and adhesion molecules leading to the accumulation of leukocytes (macrophages, neutrophils and interferon-γ producing T cells). Endothelial cells and activated macrophages produce growth factors, which together with interferon-γ produced by T cells (and subsequently in autonomic loop by macrophages and SMCs), stimulate the SMCs residing in the media to acquire proliferative phenotype and migrate to the intima. This leads to progressive loss of SMCs from the media and thickening of the intima (formation of the neointima). (b) In the “outside-in” hypothesis the inflammatory response is initiated at the adventitia and progresses inward. Signaling from the inflamed adventitia leads to apoptosis of resident SMCs of media. In addition, it results in the production of cytokines and growth factors, which induce phenotypic switch of adventitia progenitor/stem cells and/ or resident fibroblasts into migratory cells; which migrate to the intima, proliferate, and differentiate into SMCs.