Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis

Abstract

The clinical complications of atherosclerosis are caused by thrombus formation, which in turn results from rupture of an unstable atherosclerotic plaque. The formation of microvessels (angiogenesis) in an atherosclerotic plaque contributes to the development of plaques, increasing the risk of rupture. Microvessel content increases with human plaque progression and is likely stimulated by plaque hypoxia, reactive oxygen species and hypoxia-inducible factor (HIF) signalling. The presence of plaque hypoxia is primarily determined by plaque inflammation (increasing oxygen demand), while the contribution of plaque thickness (reducing oxygen supply) seems to be minor. Inflammation and hypoxia are almost interchangeable and both stimuli may initiate HIF-driven angiogenesis in atherosclerosis. Despite the scarcity of microvessels in animal models, atherogenesis is not limited in these models. This suggests that abundant plaque angiogenesis is not a requirement for atherogenesis and may be a physiological response to the pathophysiological state of the arterial wall. However, the destruction of the integrity of microvessel endothelium likely leads to intraplaque haemorrhage and plaques at increased risk for rupture. Although a causal relation between the compromised microvessel structure and atherogenesis or between angiogenic stimuli and plaque angiogenesis remains tentative, both plaque angiogenesis and plaque hypoxia represent novel targets for non-invasive imaging of plaques at risk for rupture, potentially permitting early diagnosis and/or risk prediction of patients with atherosclerosis in the near future.

The role of resistin as a regulator of inflammation: Implications for various human pathologies

“…Angiogenesis in an atherosclerotic plaque contributes to its vulnerability, which may lead to rupture and subsequent intra-arterial occlusion [89]. In contrast, revascularization and collateral circulation is a desired process in the ischemic heart muscle and limb and is becoming the therapeutic goal [90].…”

Vascular imaging with positron emission tomography

“…Glucose uptake of macrophages is significantly higher than that of neighbouring cell types [16][17][18]. They can also metabolize free fatty acids but in the anaerobic environment of the plaque [19], preferentially use glucose, as this does not require oxygen to produce ATP [20]. Compared with quiescent cells, activated macrophages show an increased expression of GLUT type 1 and type 3 receptors, along with hexokinase [21][22][23].…”

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

“…Hypoxia, due to intimal thickening causing reduced oxygen diffusion, combined with higher oxygen requirements of metabolically active inflammatory cells, is believed to trigger neovascularization by inducing the expression of hypoxia-inducible transcription factor and vascular endothelial growth factor in macrophages [10]. However, these new vessels are structurally immature, leaky, and prone to rupture [11]. This promotes leukocyte infiltration and predisposition to intra-plaque hemorrhage, which is an independent predictor of future cardiovascular outcomes [12].…”