Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization

The causes of progression from an asymptomatic fi broatheromatous lesion to a high-risk vulnerable plaque are not fully understood, but data suggest that intraplaque hemorrhage could be critical in this process. Here, Jain et al . focus on angiogenesis and intraplaque hemorrhage in atherosclerotic lesion progression. They discuss evidence for the role of antiangiogenic agents in normalizing the immature vasculature and examine the obstacles faced in testing their hypothesis both in preclinical models and in humans. Angiogenesis within human atherosclerotic plaques has an important role in plaque progression as immature blood vessels leak red blood cells and inflammatory mediators into the plaque center. Accumulation of free cholesterol from red blood cell membranes potentially increases the size of the necrotic core and triggers a chain of events that promote plaque destabilization. Antiangiogenic agents have been shown to prune some tumor vessels and 'normalize' the structure and function of the remaining vasculature, thereby improving the access of chemotherapeutic agents to tumors. We propose that antiangiogenic therapy can similarly stabilize vulnerable 'rupture-prone' plaques by pruning and normalizing immature intraplaque vessels, preventing further intraplaque hemorrhage. This normalization would limit necrotic core enlargement, further luminal narrowing and the degree of inflammation. Such normalization has been realized using vascular endothelial growth factor antagonists for the treatment of cancer and age-related macular degeneration. The development of this novel approach to prevent plaque progression might add to the armamentarium of preventive measures for acute myocardial infarction, stroke and sudden cardiac death. Key Points Although the causes of atherosclerotic lesion progression from an asymptomatic fibroatheromatous plaque to a lesion at high risk of rupture (thin-cap fibroatheroma or 'vulnerable plaque') are not fully understood, data support the concept that intraplaque hemorrhage is critical for the progression of plaques into high-risk unstable lesions On the basis of similarities with the structure of tumor vessels, we propose that judicious application of antiangiogenic agents could prune and normalize immature intraplaque blood vessels, thereby preventing intraplaque hemorrhage A similar paradigm has been described in the wet form of age-related macular degeneration; pegaptanib, a aptamer that inhibits vascular endothelial growt