Hypoxia-inducible factor pathway and diseases of the vascular wall

Background: Hypoxia may contribute to the pathogenesis of various diseases of the vascular wall. Hypoxia-inducible factors (HIFs) are nuclear transcriptional factors that regulate the transcription of genes that mediate cellular and tissue homeostatic responses to altered oxygenation. This article reviews the published literature on and discusses the role of the HIF pathway in diseases involving the vascular wall, including atherosclerosis, arterial aneurysms, pulmonary hypertension, vascular graft failure, chronic venous diseases, and vascular malformation.

Methods: PubMed was searched with the terms "hypoxia-inducible factor" or "HIF" and "atherosclerosis," "carotid stenosis," "aneurysm," "pulmonary artery hypertension," "varicose veins," "venous thrombosis," "graft thrombosis," and "vascular malformation."

Results: In atherosclerotic plaque, HIF-1α was localized in macrophages and smooth muscle cells bordering the necrotic core. Increased HIF-1α may contribute to atherosclerosis through alteration of smooth muscle cell proliferation and migration, angiogenesis, and lipid metabolism. The expression of HIF-1α is significantly elevated in aortic aneurysms compared with nonaneurysmal arteries. In pulmonary hypertension, HIF-1α contributes to the increase of intracellular K(+) and Ca(2+) leading to vasoconstriction of pulmonary smooth muscle cells. Alteration of the HIF pathway may contribute to vascular graft failure through the formation of intimal hyperplasia. In chronic venous disease, HIF pathway dysregulation contributes to formation of varicose veins and venous thromboembolism. However, whether the activation of the HIF pathway is protective or destructive to the venous wall is unclear. Increased activation of the HIF pathway causes aberrant expression of angiogenic factors contributing to the formation and maintenance of vascular malformations.

Conclusions: Pathologic vascular wall remodelling of many common diseases of the blood vessels has been found to be associated with altered activity of the HIF pathway. Therefore, understanding the role of the HIF pathway in diseases of the vascular wall is important to identify novel therapeutic strategies in the management of these pathologies.