Hypoxia in Atherogenesis

Abstract

The anoxemia theory 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. There is now substantial evidence that there are regions within the atherosclerotic plaque in which profound hypoxia exists; this may fundamentally change the function, 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)-1α; a subunit of the hetero-dimeric nuclear transcriptional factor HIF-1; a master regulator of oxygen homeostasis.HIF-1 expression is localized to perivascular tissues, inflammatory macrophages and smooth muscle cells adjacent to the necrotic core of atherosclerotic lesions, and regulates several genes that are important to vascular function including vascular endothelial growth factor (VEGF), nitric oxide synthase (NOS), endothelin-1 and erythropoietin (EPO). This review summarizes the effects of hypoxia on the functions of cells involved in atherogenesis, and the evidence for its potential importance from experimental models and clinical studies.

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

“…In this regard, the anoxemia theory is defined as a condition of abnormal oxygenation of the arterial blood. This theory proposes that an imbalance between the demand for and supply of O 2 in the arterial wall is a critical factor in the development of atherosclerosis [105]. As a consequence, macrophages become apoptotic, a necrotic core is built, and there is an eventual increase in angiogenesis, linking senescent cells to atherosclerosis progression [7].…”

“…If the O 2 supply is restored, HIF-1α is degraded, which reduces VEGF production and subsequent angiogenic signaling [107]. Another study reported that HIF-1α increases as a consequence of neovascularization in complicated human atherosclerosis among human carotids, as well as in coronary plaques [105]. Mechanistically, the angiogenic effect of the alternatively spliced tissue factor (asTF) activates HIF-1/VEGF signaling [41].…”

A Human Long Non-Coding RNA ALT1 Controls the Cell Cycle of Vascular Endothelial Cells Via ACE2 and Cyclin D1 Pathway

“…Although the underlying mechanism of increasing HIF-1α level by ALT1 knockdown remains unknown, ALT1 level was found to be down regulated by hypoxia, and cell contact inhibition ( in vitro ) in HUVECs. Hypoxia might be caused by imbalance between supply and consumption of oxygen [30]. It was proposed that hypoxia caused by imbalance between oxygen consumption and supply in arterial wall plays key roles in atherosclerosis development [30, 31].…”

“…Hypoxia might be caused by imbalance between supply and consumption of oxygen [30]. It was proposed that hypoxia caused by imbalance between oxygen consumption and supply in arterial wall plays key roles in atherosclerosis development [30, 31]. ALT1 level reduction caused by hypoxia might be one of the mechanisms underlying endothelial dysfunction caused by hypoxia during the early stage of atherosclerosis development.…”

Hypoxia, Angiogenesis and Atherogenesis

“…The vasa vasorum, forming the network of small blood vessels, are vulnerable to hypoxia espe-cially at the site of arterial branching as they are end arteries and the blood flow is reduced in this region. It has been hypothesized that hypoxia within the vasa vasorum is due to reduced blood flow and consequent endothelial dysfunction, local inflammation and permeation of large particles such as microbes, LDL-lipoprotein and fatty acids which are transformed by macrophages into foam cells [63,64], which may be an initiating factor in atherosclerosis [65]. Therefore, the micro-environment within the atherosclerotic plaque is thought to be an important determinant of whether a plaque progresses, and the likelihood of clinical complications.…”