Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness

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.

Figure 1

Diagram of possible VSMC phentoypes and their cellular/disease/organotypic origin. Diagrammatic representation of the spectrum of VSMC phenotypes identified during calcification (bold), their cellular markers and phenotypic drivers in red. Dexamethasone (D), Methylisobutylxanthine (M), and insulin (I).

Figure 2

VSMC differentiation in intimal and medial calcification. (A) Within the medial layer the VSMC cells respond to osteogenic stimuli, e.g. prolonged uraemia, and differentiate into osteoblast-like cells. These subsequently produce macrocalcification deposits within the medial layer of the blood vessel causing stiffening of the vessel wall. (B) Atherosclerosis is characterized by lipid deposition between the intimal and medial layers of the blood vessel, which subsequently leads to macrophage infiltration, as well as the differentiation of VSMCs into foam cells. Inflammation, apoptosis, and oxidative stress subsequently lead to VSMC differentiation into osteoblast-like cells which, in turn, leads to microcalcification deposits within the intimal wall, weakening the structure of the wall and increasing the risk of plaque rupture.