Abstract
Atherosclerosis and vascular disease of larger arteries are often associated with hypoxia within the layers of the vascular wall. In this review, we begin with a brief overview of the molecular changes in vascular cells associated with hypoxia and then emphasize the transport mechanisms that bring oxygen to cells within the vascular wall. We focus on fluid mechanical factors that control oxygen transport from lumenal blood flow to the intima and inner media layers of the artery, and solid mechanical factors that influence oxygen transport to the adventitia and outer media via the wall's microvascular system—the vasa vasorum (VV). Many cardiovascular risk factors are associated with VV compression that reduces VV perfusion and oxygenation. Dysfunctional VV neovascularization in response to hypoxia contributes to plaque inflammation and growth. Disturbed blood flow in vascular bifurcations and curvatures leads to reduced oxygen transport from blood to the inner layers of the wall and contributes to the development of atherosclerotic plaques in these regions. Recent studies have shown that hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor associated with hypoxia, is also activated in disturbed flow by a mechanism that is independent of hypoxia. A final section of the review emphasizes hypoxia in vascular stenting that is used to enlarge vessels occluded by plaques. Stenting can compress the VV leading to hypoxia and associated intimal hyperplasia. To enhance oxygen transport during stenting, new stent designs with helical centrelines have been developed to increase blood phase oxygen transport rates and reduce intimal hyperplasia. Further study of the mechanisms controlling hypoxia in the artery wall may contribute to the development of therapeutic strategies for vascular diseases.
Highlights
Introduction and backgroundThe hypoxia theory of atherosclerosis proposes that an imbalance between the demand for and supply of oxygen in the arterial wall is a key factor in the development of intimal hyperplasia and atherosclerotic plaques
Under normoxic conditions, Hypoxia-inducible factor-1α (HIF-1α) becomes targeted for degradation through proline hydroxylation by HIF prolyl hydroxylase (PHD) which results in a conformational change promoting its binding to Von Hippel–Lindau disease tumour suppressor protein (VHL) E3 ligase complex, which in turn targets HIF-1α for ubiquitination and rapid royalsocietypublishing.org/journal/rsif J
Hypoxia in the vascular wall leads to the upregulation of the transcription factor HIF-1α that induces pro-atherogenic genes enhancing cell proliferation, inflammation and angiogenesis
Summary
The hypoxia theory of atherosclerosis proposes that an imbalance between the demand for and supply of oxygen in the arterial wall is a key factor in the development of intimal hyperplasia and atherosclerotic plaques. It is not surprising that hypoxia and inflammation share common signalling pathways; of major importance is NF-кB activation It was first reported in 1994 by Koong et al [5] that hypoxia activates NF-кB signalling by triggering the degradation of inhibitory IкB-a, resulting in the release of p65 (RelA) from the inhibitory complex and translocation into the nucleus where it promotes the transcription of NF-кB target genes. HIF-1α triggers endothelial–mesenchymal transition [12,13], a process that results in further enhancement of inflammation, proliferation and permeability and has been shown to trigger atherosclerosis [14,15] All of these changes in endothelial cell function are a hallmark of a dysfunctional endothelium which leads to the development of atherosclerosis. A final section describes the biophysical effects of a stent with a helical centreline that promotes enhanced oxygen transport to the inner layers of the wall by virtue of the secondary flows induced by the helical geometry and reduces intimal hyperplasia
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