Available online 29 November 2022, 107510

Author links open overlay panelABSTRACT

Atherogenesis involves a complex multifactorial process including chronic inflammation that requires the participation of several cell types and molecules. In addition to their role in vascular homeostasis, extracellular vesicles also appear to play an important role in atherogenesis, including monocyte transmigration and foam cell formation, SMC proliferation and migration, leukocyte transmigration, and thrombosis. Peripheral arterial disease, a major form of peripheral vascular disease, is characterized by structural or functional impairment of peripheral arterial supply, often secondary to atherosclerosis. Elevated levels of extracellular vesicles have been demonstrated in patients with peripheral arterial disease and implicated in the development of atherosclerosis within peripheral vascular beds. However, extracellular vesicles also appear capable of delivering cargo with atheroprotective effects. This capability has been exploited in vesicles engineered to carry content capable of neovascularization, suggesting potential for therapeutic angiogenesis. This dual capacity holds substantial promise for diagnosis and therapy, including possibly limb- and life-saving options for peripheral arterial disease management.

Section snippetsINTRODUCTION

Throughout the last few decades, the central concepts and key targets of atherogenesis, have expanded from a focus on lipid deposition [1], [2], [3], to the role of chronic inflammation [1], [2], [3], [4], [5] and more recently autoimmunity [5, 6]. As a result, atherogenesis is now understood to represent a complex multifactorial process characterized by underlying chronic inflammation and involving several key cell types including vascular endothelial cells, vascular smooth muscle cells

METHODS

Searches of PubMed and Web of Science were performed. The search strategy included the terms extracellular vesicles, extracellular vesicle, exosomes, exosome, microparticles, microparticle, microvesicles, microvesicle, apoptotic bodies and apoptotic body, each in combination with peripheral arterial disease as well as peripheral artery disease. Articles were filtered by an initial assessment of their abstracts, with subsequent selection based on relevance to the review objective. Additional

RESULTS

The study flowchart is presented in Figure 1. A total of 49 unique articles were identified. Of these, 14 articles were reviews and a further 13 articles were excluded because of lack of relevance to the review objectives. The remaining 22 articles (Table 1) were the focus of this review.

ECV BIOLOGY

ECVs are microscopic phospholipid bilayer-encircled particles ranging in size from ∼30nm to 5μm, and are derived from most cell types [25]. Central to their biology is vesicular movement between source and recipient cells. This inter-cellular path, from biogenesis, through cellular release, to uptake by recipient cells, has been extensively reviewed by others [26], [27], [28], and illustrated in Figure 2. Briefly, exosome biogenesis occurs within the endosomal system, with early endosomes

ECVS AND ATHEROSCLEROSIS

Considering the cellular origins of ECVs, pathological cells associated with pathological states, will produce ECVs with altered properties and functions. With respect to endothelial pathology, altered circulating ECVs would be prime candidates to contribute to development of known features of endothelial dysfunction, including inflammation, impaired vasodilation, and coagulation [16, 51], thereby promoting atherosclerosis. For example, both CD45+ (leukocyte-derived) and CD31 (PECAM-1)+ ECVs

ATHEROSCLEROTIC PERIPHERAL ARTERIAL DISEASE AND ECVS

PAD is one of the major types of peripheral vascular disease, characterized by structural or functional impairment of the arterial supply to tissues excluding the heart and brain [74]. Although peripheral arteries may be more resistant to atherosclerosis compared with other vascular beds, the etiology of PAD is dominated by intraluminal pathology involving atherosclerosis and/or thrombosis [75]. Less common causes include arteritis (e.g., large- and medium-vessel vasculitides, and

CONCLUSION

Our knowledge of ECV biology and ECV-mediated pathology is evolving. With respect to atherosclerosis, the role of ECVs in peripheral arterial disease implies a duality with both pro-atherogenic and atheroprotective potential. The evidence indicates that ECVs carry pro-atherogenic cargo. However, ECVs also demonstrate angiogenic potential. The latter appears to be partly physiological, representing a natural response to ischemic injury. However, the atheroprotective potential can be

Funding

This paper did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT author statement

PAB: Conceptualization, Writing - Original Draft, Writing - Review & Editing, Visualization, Final Approval; PDB: Writing - Review & Editing, Final Approval

Ethics Approval and Informed Consent

Not applicable as this is a review article.

CRediT authorship contribution statement

Paul A Brown: Conceptualization, Writing – original draft, Writing – review & editing, Visualization. Paul D Brown: Writing – review & editing.

Competing Interests

The authors report no conflicts of interest in this work.

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