Vascular calcification: Mechanisms of vascular smooth muscle cell calcification

Abstract

Vascular calcification is highly prevalent and, when present, is associated with major adverse cardiovascular events. Vascular smooth muscle cells play an integral role in mediating vessel calcification by undergoing differentiation to osteoblast-like cells and generating matrix vesicles that serve as a nidus for calcium-phosphate deposition in the vessel wall. Once believed to be a passive process, it is now recognized that vascular calcification is a complex and highly regulated process that involves activation of cellular signaling pathways, circulating inhibitors of calcification, genetic factors, and hormones. This review will examine several of the key mechanisms linking vascular smooth muscle cells to vessel calcification that may be targeted to reduce vessel wall mineralization and, thereby, reduce cardiovascular risk.

Figure 1. Vascular calcification predicts cardiovascular events

In a meta- analysis, risk for major adverse events was determined for patients with cardiovascular calcification versus those without calcification. Data from 218,080 patients from 30 studies was examined to determine the odds ratio (OR) for all-cause and cardiovascular (CV) mortality as well as any CV event, stroke, or coronary events. Patients included in these studies ranged from asymptomatic individuals to those with diabetes mellitus, chronic kidney disease, chest pain and multiple risk factors. Adapted with permission fromRennenberg, et al. Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis. Vasc Health Risk Manage 2009;5:185-97. (6)

Figure 2. Matrix vesicles initiate vascular calcification

In vascular smooth muscle cells (SMC) exposed to high levels of phosphate, which is taken up by the phosphate transporter PIT1, SMC undergo differentiation to osteoblast-like cells and express the master osteoblast transcription factor Runx2. These SMC generate matrix vesicles that deposit in the vessel wall and serve as a site for nucleation and vascular medial calcification. These membrane-bound matrix vesicles include proteins for calcium and phosphate import and related to extracellular (ECM) mineralization, cytoskeleton, cellular stress and other intracellular proteins. Adapted with permission from Kapustin, et al. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ Res 2011;109:e1-12. (27)

Figure 3. Mechanisms of vascular medial calcification

Contractile vascular smooth muscle cells undergo differentiation to osteoblast-like cells when exposed to high levels of phosphate and other cellular and/or systemic processes that facilitate vascular calcification. These osteoblast-like cells participate in vascular medial calcification.