Abstract
Vascular calcification is associated with a significant increase in all-cause mortality and atherosclerotic plaque rupture. Calcification has been determined to be an active process driven in part by vascular smooth muscle cell (VSMC) transdifferentiation within the vascular wall. Historically, VSMC phenotype switching has been viewed as binary, with the cells able to adopt a physiological contractile phenotype or an alternate ‘synthetic’ phenotype in response to injury. More recent work, including lineage tracing has however revealed that VSMCs are able to adopt a number of phenotypes, including calcific (osteogenic, chondrocytic, and osteoclastic), adipogenic, and macrophagic phenotypes. Whilst the mechanisms that drive VSMC differentiation are still being elucidated it is becoming clear that medial calcification may differ in several ways from the intimal calcification seen in atherosclerotic lesions, including risk factors and specific drivers for VSMC phenotype changes and calcification. This article aims to compare and contrast the role of VSMCs in driving calcification in both atherosclerosis and in the vessel media focusing on the major drivers of calcification, including aging, uraemia, mechanical stress, oxidative stress, and inflammation. The review also discusses novel findings that have also brought attention to specific pro- and anti-calcifying proteins, extracellular vesicles, mitochondrial dysfunction, and a uraemic milieu as major determinants of vascular calcification.
Highlights
1.1 Vascular calcificationVascular calcification, the deposition of hydroxyapatite mineral in the arterial wall, is linked to an increased risk of heart disease, stroke, atherosclerotic plaque rupture.[1]
Intimal and medial calcification are increased in patients with Type 1 (T1D) and Type 2 diabetes (T2D)/metabolic syndrome (MetS), chronic kidney disease (CKD), and postmenopausal women affected by osteoporosis
The resulting oxidative products may activate the NF-jB-RankL pathways provoking the production of procalcific cytokines, such as tumour necrosis factor-a (TNFa), IL-6, and IL-1b,102–104 or induce mitochondrial DNA damage[87] and apoptosis of surrounding cells, such as vascular smooth muscle cell (VSMC),[87] both of which contribute to the development of arterial intimal calcification (AIC)
Summary
The deposition of hydroxyapatite mineral in the arterial wall, is linked to an increased risk of heart disease, stroke, atherosclerotic plaque rupture.[1] Calcification occurs in both the intimal and medial layers of the arteries. In addition to accelerated CAC, patients with diabetes (T1D and T2D) develop extensive medial calcification of the peripheral arteries of the feet and legs. The mechanisms driving this localized calcification response are poorly understood and likely include novel factors in addition to hyperglycaemia, such as neuropathy.[7]. Aberrant levels of osteoprotegerin, sclerostin, or FGF-23 may explain and predict the occurrence of both osteoporotic fractures and cardiovascular events.[15,17]
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