Hypoxia, angiogenesis and atherogenesis

The balance between vascular oxygen supply and metabolic demand for oxygen within the vasculature is normally tightly regulated. An imbalance leads to hypoxia and a consequential cascade of cellular signals that attempt to offset the effects of hypoxia. Hypoxia is invariably associated with atherosclerosis, wound repair, inflammation and vascular disease. The anoxaemia hypothesis proposes that an imbalance between the demand for and supply of oxygen in the arterial wall is a key factor in the development of atherosclerosis and plaque angiogenesis. There is now substantial evidence that hypoxia plays an essential role in angiogenesis as well as plaque angiogenesis. It controls the metabolism, and responses of many of the cell types found within the developing plaque and whether the plaque will evolve into a stable or unstable phenotype. Hypoxia is characterized in molecular terms by the stabilization of hypoxia-inducible factor (HIF) 1a, a subunit of the heterodimeric nuclear transcriptional factor HIF-1 and a master regulator of oxygen homeostasis. The expression of HIF-1 is localized to perivascular tissues, inflammatory macrophages and smooth muscle cells where it regulates several genes that are important to vascular function including vascular endothelial growth factor, nitric oxide synthase, endothelin-1 and erythropoietin. This chapter summarizes the effects of hypoxia on the functions of cells involved in angiogenesis as well as atherogenesis (plaque angiogenesis) and the evidence for its potential importance from experimental models and clinical studies.