Extracellular Vesicle-Mediated Angiogenesis in Peripheral Artery Disease: Context-Dependent Effects in Ischemic Limbs and Atherosclerotic Plaques

Peripheral artery disease (PAD) is most commonly caused by atherosclerotic arterial stenosis or occlusion, which reduces downstream tissue perfusion and causes tissue ischemia. In response to ischemia, reparative angiogenesis is activated and may support tissue perfusion recovery and skeletal muscle protection. In contrast, neovascularization within atherosclerotic plaques may promote intraplaque hemorrhage and plaque destabilization. Thus, angiogenesis has dual roles in PAD-related ischemia and atherosclerotic plaques. Extracellular vesicles (EVs) are membrane-bound particles that carry various cargo, including proteins, lipids, nucleic acids, and metabolites. Through the transfer of bioactive cargo and surface-mediated signaling, EVs can modify recipient-cell functions and thereby influence angiogenic signaling. Investigation of EV-mediated communication may therefore help elucidate the mechanisms underlying angiogenic regulation in vascular disease. In addition, disease-promoting EVs may be therapeutically targeted, whereas engineered EVs may be developed as therapeutic agents or delivery platforms. Recent studies have shown that EVs regulate angiogenic responses in preclinical murine hindlimb ischemia models. However, these effects in ischemic limbs and the potential involvement of EVs in atherosclerotic plaque neovascularization have rarely been reviewed in an integrated manner. This narrative review discusses these contrasting angiogenic processes from a context-dependent perspective. Understanding this context dependency may help develop EV-based strategies that promote functional vascular repair in ischemic tissues while suppressing or normalizing pathological neovascularization in atherosclerotic plaques.