The Role of Angiogenesis in Coronary Artery Disease: A Double-edged Sword: Intraplaque Angiogenesis in Physiopathology and Therapeutic Angiogenesis for Treatment

Angiogenesis is described as a sprouting and growth process of new blood vessels from pre-existing vasculature. The relationship between angiogenesis and coronary artery disease (CAD) is double-sided. On one hand, angiogenesis within plaques is responsible for facilitating the growth and vulnerability of plaques by causing intraplaque hemorrhage and inflammatory cell influx, and overabundance of erythrocytes and inflammatory cells within a plaque probably causes plaque rupture, further leading to acute coronary syndrome. Therefore, inhibiting intraplaque angiogenesis has been considered as a potential therapeutic target for CAD. On the other hand, aiming at improving reperfusion to the ischemic myocardium in patients with CAD, angiogenesis promoting has been utilized as a therapeutic approach to expand myocardial microvascular network. Current strategies include direct administration of angiogenic growth factors (protein therapy), promoting angiogenic genes expression in vivo (gene therapy), and delivering stem cells (cell therapy) or exosomes (cell free therapy). This article will start by clarifying the basic concept of angiogenesis, interpret the mechanism of excessive intraplaque angiogenesis in atherosclerosis, and discuss its role in the growth and vulnerability of plaques. Then we will focus on the four distinct strategies of therapeutic angiogenesis. Despite promising animal studies and small-scale clinical trials of therapeutic angiogenesis in patients with ischemic heart disease, investigations have far not shown definite evidence of clinical efficacy. Hence, while acknowledging future work that remains to be done to validate the clinical results, we reviewed the critical challenges in this arena and highlighted the exciting progress that has occurred recently.