Abstract

Atherosclerotic occlusive diseases and aneurysms that affect large and medium-sized arteries outside the cardiac and cerebral circulation are collectively known as peripheral arterial disease (PAD). With a rise in the rate of aging population worldwide, the number of people diagnosed with PAD is rapidly increasing. The micronutrient vitamin D is an important steroid hormone that acts on many crucial cellular mechanisms. Experimental studies suggest that optimal levels of vitamin D have beneficial effects on the heart and blood vessels; however, high vitamin D concentrations have been implicated in promoting vascular calcification and arterial stiffness. Observations from various clinical studies shows that deficiency of vitamin D has been associated with a greater risk of PAD. Epidemiological studies have often reported an inverse relation between circulating vitamin D status measured in terms of 25-hydroxivitamin D [25(OH)D] levels and increased cardiovascular disease risk; however, randomized controlled trials did not show a consistent positive effect of vitamin D supplementation on cardiovascular disease risk or events. Even though PAD shares all the major risk factors with cardiovascular diseases, the effect of vitamin D deficiency in PAD is not clear. Current evidence suggests a strong role of vitamin D in promoting genomic and epigenomic changes. This review summarises the current literature that supports the notion that vitamin D deficiency may promote PAD formation. A better understanding of underlying pathological mechanisms will open up new therapeutic possibilities which is the main unmet need in PAD management. Furthermore, epigenetic evidence shows that a more holistic approach towards PAD prevention that incorporates a healthy lifestyle, adequate exercise and optimal nutrition may be more effective in protecting the genome and maintaining a healthy vasculature.

Highlights

  • Vitamin D is an important micronutrient that is essential for optimal health throughout life

  • In a recently performed a meta-analysis on six observational studies, we showed that Peripheral arterial occlusive disease (PAOD) patients (n = 1217) had lower 25(OH)D compared to non-PAOD participants (n = 5201) [36]

  • Abdominal aortic aneurysm (AAA) is pathologically characterised by progressive degeneration of the arterial wall structure by chronic inflammation and extracellular matrix (ECM) remodelling which leads to irreversible dilatation and eventual rupture resulting in death [13,40]

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Summary

Introduction

Vitamin D is an important micronutrient that is essential for optimal health throughout life. Vitamin D, with D3 (cholecalciferol) and D2 (ergocalciferol) being the most important for human health, is obtained through two main sources, with UV light-dependent synthesis of cholecalciferol from cholesterol in the skin being the predominant source of optimal vitamin D levels (Sunlight is the major natural source of vitamin D). Of particular interest to this review, is the emerging concept of the association of vitamin D in cardiovascular health and the contribution of its deficiency towards the development and progression of peripheral arterial disease (PAD). The role of vitamin D in maintaining arterial health is assessed and the effect of vitamin deficiency on the genome and beyond is explored, with special relevance to PAD. A detailed description of the pathology of PAD is beyond the scope of this review and readers are advised to refer to the previous excellent reviews on this topic [12,13]

Vitamin D Status and PAOD Formation
Main Findings
Vitamin D Status and AAA Formation
Vitamin D Status and Mechanisms Relevant in PAD Formation
Aortic Cells and Dysfunction
Atherosclerosis
Inflammation
Arterial Stiffness and Calcification
Vitamin D Status and Angiogenesis
Vitamin D and the Genome
Vitamin D and the Epigenome
Histone Modifications
DNA Methylation
Future Direction
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