Sonodynamic Therapy Suppresses Neovascularization in Atherosclerotic Plaques via Macrophage Apoptosis-Induced Endothelial Cell Apoptosis

Abstract

• DVDMS-SDT reduces neovascularization in late-stage atherosclerotic lesions in both rabbit and mouse models. • DVDMS-SDT enhances macrophage foam cell apoptosis, which in turn induces neovessel endothelial cell apoptosis and inhibits its proliferation, migration, and tubulogenesis, termed apoptosis-induced apoptosis. • Mechanistically, DVDMS-SDT induces macrophage foam cell apoptosis via mitochondrial-caspase pathway, which activates caspase 3 to cleave SP-1, leading to the reduction of HIF-1α and VEGF-A. • In the pilot translational study, DVDMS-SDT reduces plaque angiogenesis and inhibits vessel inflammation. During atherosclerosis plaque progression, pathological intraplaque angiogenesis leads to plaque rupture accompanied by thrombosis, which is probably the most important cause of arteries complications such as cerebral and myocardial infarction. Even though few treatments are available to mitigate plaque rupture, further investigation is required to develop a robust optimized therapeutic method. In this study using rabbit and mouse atherosclerotic models, sinoporphyrin sodium (DVDMS)-mediated sonodynamic therapy reduced abnormal angiogenesis and plaque rupture. Briefly, DVDMS is injected to animals, and then the plaque was locally exposed to pulse ultrasound for a few minutes. Furthermore, a small size clinical trial was conducted on patients with atherosclerosis. Notably, a significant reduction of arterial inflammation and angiogenesis was recorded following a short period of DVDMS-mediated sonodynamic therapy treatment. This beneficial outcome was almost equivalent to the therapeutic outcome after 3-month intensive statin treatment.