The main clinical risk of atherosclerotic (As) lesions is the instability and vulnerability of plaques. Vasa vasorum (VV) inside the As plaque has structural defects, such as fragile and high leakage of vascular wall. These structural defects lead to plaque rupture and hemorrhage, which promotes inflammatory response, provides channel for leukocyte and blood soluble components entering the plaque and promotes As plaque formation. VV inside the As plaque is closely related to plaque rupture and hemorrhage, and clinical cardiovascular events. Intensive study of the VV function and its related signaling pathway in As is expected to fundamentally prevent As plaque development.