Connecting the Dots: How Injury in the Arterial Wall Contributes to Atherosclerotic Disease.

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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.

Injury to the tunica media initiates atherogenesis in the presence of hyperlipidemia.

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.

Targeting Cross-Presentation as a Route to Improve the Efficiency of Peptide-Based Cancer Vaccines.

Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1+ cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.

Stress distribution in the walls of major arteries: implications for atherogenesis.

BACKGROUND: There is a correlation between the sites of atheroma development and stress points in the arterial system. Generally, pulse pressure results in stresses acting on the vascular vessel, including longitudinal stress, radial or normal stress, tangential stress or hoop stress and shear stress. This paper explores the relationship between arterial wall shear stress and pulsatile blood pressure with the aim of furthering the understanding of atherogenesis and plaque progression. METHODS: We computed the magnitude of the shear stresses within the carotid bifurcation geometry of a patient and calculated the increase in shear stress levels that would occur when the blood pressure and pulse pressures rise during exertion. We also determined in which layer of the artery wall the maximum shear stress is located, and computed the shear stress at different levels within the media. We used the theory of laminate analysis, (Classical Laminate Plate Theory), to analyse the stress distribution on the carotid artery wall. Computational Fluid Dynamics (CFD) analysis was used on anatomy based on a CT angiogram of the carotid bifurcation of a patient with a 90% stenosis on the right side and 10% on the left. The pulsatile non-Newtonian blood flow with a resting blood pressure of 120/80 mmHg and an exertion pressure of 200/100 mmHg was simulated and the resultant forces were transferred to an ANSYS Composite PrepPost (ACP) model for wall shear stress analysis. A multilayer elastic, anisotropic, and inhomogeneous arterial wall (intima, internal elastic lamina, media, external elastic lamina, and adventitial layers) was modelled and the shear stress magnitudes and change over time between the layers was calculated. RESULTS: Shear stress in the individual composite layers is far greater than that acting on the endothelium (less than 5 Pa). At rest, the maximum variation of shear stress in the arterial wall occurs in the intima (138 Pa) and adventitia (135 Pa). The medial layer has the lowest variation of shear stress. Under severe exertion, the maximum shear stress magnitude in the intimal layer and the adjacent medial layer is near the ultimate stress level. The maximum/minimum shear stress ratios during the cardiac cycle vary most widely in the innermost part of the media, adjacent to the intima, with a four-fold ratio increase. This compares with a less than two-fold increase in all the other layers including the intima and adventitia, making the inner media the most vulnerable layer to mechanical injury. CONCLUSIONS: This study showed that the magnitude of exertion-induced shear stress approaches the ultimate stress limit in the intima and the immediate adjacent medial layer. The variation in stress is maximal in the inner layer of the media. These findings correlate the site of atheroma development with the most vulnerable site for injury in the media and emphasise the impact of pulse pressure. Further biological studies are required to ascertain whether this leads to injury that initiates atheroma that then precipitates an injury/healing cycle.

Major gaps in human evidence for structure and function of the vasa vasora limit our understanding of the link with atherosclerosis.

Atherosclerosis is the major pathology causing death in the developed world and, although risk factor modification has improved outcomes over the last decade, there is no cure. The role of the vasa vasora (VV) in the pathogenesis of atherosclerotic plaque is unclear but must relate to the predictability of diseased sites in the arterial tree. VV are small vessels found on major arteries and veins which supply nutrients and oxygen to the vessel wall itself while removing waste. Numerous studies have been carried out to investigate the anatomy and function of the VV as well as their significance in vascular disease. There is convincing evidence that VV are related to atherosclerotic plaque progression and vessel thrombosis, however, their link to the pathology of plaque initiation remains an interesting but neglected topic. We aim to present the evidence on the anatomy and functional behaviour of VV as well as their relationship to the initiation of atherosclerosis. At the same time, we wish to highlight inconsistencies in, and limitations of, the evidence available.