Vasa vasorum in atherosclerosis and clinical significance

Abstract

Atherosclerosis is a chronic inflammatory disease that leads to several acute cardiovascular complications with poor prognosis. For decades, the role of the adventitial vasa vasorum (VV) in the initiation and progression of atherosclerosis has received broad attention. The presence of VV neovascularization precedes the apparent symptoms of clinical atherosclerosis. VV also mediates inflammatory cell infiltration, intimal thickening, intraplaque hemorrhage, and subsequent atherothrombosis that results in stroke or myocardial infarction. Intraplaque neovessels originating from VV can be immature and hence susceptible to leakage, and are thus regarded as the leading cause of intraplaque hemorrhage. Evidence supports VV as a new surrogate target of atherosclerosis evaluation and treatment. This review provides an overview into the relationship between VV and atherosclerosis, including the anatomy and function of VV, the stimuli of VV neovascularization, and the available underlying mechanisms that lead to poor prognosis. We also summarize translational researches on VV imaging modalities and potential therapies that target VV neovascularization or its stimuli.

Keywords: angiogenic therapy; atherosclerosis; imaging modality; mechanism; neovascularization; vasa vasorum.

Figure 1

Scheme of first-order VV, second-order VV, and main coronary artery.

Figure 2

Intimal thickening, decreased blood supply (due to high pressure in parent vessel and the stimulated constriction of VV, represented by grey arrows in the left closed box) and active metabolism of inflammatory cells together contribute to hypoxia in atherosclerotic vessels (left panel). The oxygen-insufficient microenvironment in inner layers of vessel wall further induces angiogenesis through activating HIF, VEGF-A and Ets signaling pathways. As a result, the formation of intraplaque neovessels originating from VV leads to the progression of atherosclerotic plaques, including intraplaque hemorrhage, lipid core enlargement, inflammatory cell infiltration, and ultimate rupture (right panel).