The unstable plaque: a broken balance

Abstract

Atherogenesis is traditionally traced to endothelial dysfunction, secondary to the interaction between intravascular factors and the luminal vessel surface. Dyslipidaemia, hypertension, smoking, inflammatory cytokines, and advanced glycation endproducts are thought to negatively modify blood and, consequently, the vascular intima. Ensuing endothelial activation and dysfunction are characterized by reduced nitric oxide bioavailability, generation of reactive oxygen species (ROS), expression of prothrombotic and leukocyte adhesion molecules, subendothelial lipid, mononuclear and smooth muscle cell accumulation, and impaired oxygen diffusion from the bloodstream into a thickened and ailing intima.1 Plaque rupture is also traditionally linked to events within the vascular intima, including fibrous cap thinning, necrotic core expansion, weakened shoulder regions, and sudden bursts of proteases by resident inflammatory cells.2 Yet, a large part of the vessel wall is represented by the media and adventitia, perfused by vasa vasorum that supply the outer layers. Proliferation of these neovessels has been recognized for some time to characterize atheromatous lesions.3 This is not surprising, since intramural hypoxia, inflammation, and apoptosis induce factors (such as vascular endothelial growth factor, platelet-derived growth factor, and transforming growth factor) that promote, within a local pro-angiogenic milieu, the sprouting of new vessels from existing capillaries.3–5 This predominantly ischaemia-driven process can be viewed as initially compensatory, aimed at restoring oxygen availability and at resolving inflammatory/necrotic foci ( Figure 1 ). Figure 1 Hypothetical pathophysiological pathway in stable and unstable plaques. In stable plaques, intramural hypoxia and chronic inflammation induce sprouting of immature microvessels from vasa vasorum that leak blood into the interstitium. Haptoglobin–haemoglobin complexes are cleared by CD163-expressing macrophages. These cells exert antioxidant, anti-inflammatory, and scavenger functions that maintain a ‘stable balance’ between production and removal of debris and of reactive oxygen species. In unstable plaques, acute inflammation enhances hypoxia-induced neovascularization, … *Corresponding author. Tel: +39 06 305 11 66, Fax: +39 (06) 305 5535, E-mail: filippo.crea{at}rm.unicatt.it