Tension in the Plaque: Hypoxia Modulates Metabolism in Atheroma

Abstract

Investigators have long recognized low oxygen tension in the atherosclerotic plaque. The diffusion limitation for molecular oxygen through the relatively avascular center of the plaque decreases the supply of this gas. Inflammatory cells accumulate in the core of atheromata. These cells have high metabolic rates and correspondingly high oxygen consumption, increasing demand (Figure). Human and experimental atheromata have hypoxic regions. Animal studies have shown that hypoxia augments atherogenesis.1,2 Recent work has highlighted the myriad mechanisms by which hypoxia may contribute to atheroma evolution and complication.3,4 Figure. Hypoxia in atherogenesis. This figure illustrates selected examples of the manifold effects of hypoxia in atheromata; see text for explanation. 15-LOX-2 indicates 15-lipoxygenase-2; ABCA1, ATP-binding cassette A 1; FA, fatty acid; GLUT-1, glucose transporter 1; HIF-1α, hypoxia-inducible factor 1α; HMG-CoA, hydroxymethylglutaryl coenzyme A; IL, interleukin; MMP, matrix metalloproteinase; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor. Pathologists have long appreciated the microvasculature of plaques. The rise of Judah Folkman's concept of tumor angiogenesis as a growth-promoting mechanism in malignancy stimulated parallel thinking in atherosclerosis research.5 Plaque neovessels may stimulate lesion growth and provide a portal with a large surface area for penetration of inflammatory cells. Fragile neovessels in atheromata, as in the diabetic retina, may prove prone to hemorrhage. Extravasated erythrocytes furnish a local depot of cholesterol-rich red cell membranes and of heme, a source of iron—which is a catalyst for oxidative stress. Thrombosis in situ may elicit cycles of thrombin-mediated smooth-muscle cell (SMC) migration and proliferation and hence lesion growth. Thus the neovessels stimulated through the …