The occurrence and development of atherosclerotic cardiovascular disease, which can result in severe outcomes, such as myocardial infarction, stroke, loss of limb, renal failure, and infarction of the gut, are strongly associated with injury to the intimal component of the arterial wall whether via the inside-out or outside-in pathways. The role of injury to the tunica media as a pathway of atherosclerosis initiation is an underresearched area. This review focuses on potential pathways to vessel wall injury as well as current experimental and clinical research in the middle-aged and elderly populations, including the role of exercise, as it relates to injury to the tunica media. A database search using PubMed and Google Scholar was conducted for research articles published between 1909 and 2023 that focused on pathways of atherogenesis and the impact of mechanical forces on wall injury. The following key words were searched: wall injury, tunica media, atherogenesis, vascular aging, and wall strain. Studies were analyzed, and the relevant information was extracted from each study. A link between high mechanical stress in the arterial wall and reduced vascular compliance was found. The stiffening and calcification of the arterial wall with aging induce high blood pressure and pulse pressure, thereby causing incident hypertension and cardiovascular disease. In turn, prolonged high mechanical stress, particularly wall strain, applied to the arterial wall during vigorous exercise, results in stiffening and calcification of tunica media, accelerated arterial aging, and cardiovascular disease events. In both scenarios, the tunica media is the primary target of mechanical stress and the first to respond to hemodynamic changes. The cyclical nature of these impacts confounds the results of each because they are not mutually exclusive. The role of stress in the tunica media appears to be overlooked despite its relevance, and further research into new primary preventive therapies is needed aside from cautioning the role of vigorous exercise in the elderly population.

Background and aims: Fatty streaks initiating the formation of atheromatous plaque appear in the tunica intima. The tunica media is not known to be a nidus for lipid accumulation initiating atherogenesis. We assessed changes to the tunica media in response to a micro-injury produced in the pig aorta. In addition, we assessed human carotid endarterectomy plaques for indication of atheroma initiation in the tunica media.Methods: Three healthy landrace female pigs underwent laparotomy to inject autologous blood and create micro-hematomas at 6 sites within the tunica media of the infrarenal abdominal aorta. These pigs were fed a high-fat diet (HFD) for 4–12 weeks. Post-mortem aortas from all pigs, including a control group of healthy pigs, were serially stained to detect lipid deposits, vasa vasora (VV), immune cell infiltration and inflammatory markers, as well as changes to the vascular smooth muscle cell (vSMC) compartment. Moreover, 25 human carotid endarterectomy (CEA) specimens were evaluated for their lipid composition in the tunica media and intima.Results: High lipid clusters, VV density, and immune cell infiltrates were consistently observed at 5 out of 6 injection sites under prolonged hyperlipidemia. The hyperlipidemic diet also affected the vSMC compartment in the tunica media adjacent to the tunica adventitia, which correlated with VV invasion and immune cell infiltration. Analysis of human carotid specimens post-CEA indicated that 32% of patients had significantly greater atheroma in the tunica media than in the arterial intima.Conclusion: The arterial intima is not the only site for atherosclerosis initiation. We show that injury to the media can trigger atherogenesis.