Cell Phenotype Transitions in Cardiovascular Calcification

Abstract

Cardiovascular calcification was originally considered a passive, degenerative process, however with the advance of cellular and molecular biology techniques it is now appreciated that ectopic calcification is an active biological process. Vascular calcification is the most common form of ectopic calcification, and aging as well as specific disease states such as atherosclerosis, diabetes, and genetic mutations, exhibit this pathology. In the vessels and valves, endothelial cells, smooth muscle cells, and fibroblast-like cells contribute to the formation of extracellular calcified nodules. Research suggests that these vascular cells undergo a phenotypic switch whereby they acquire osteoblast-like characteristics, however the mechanisms driving the early aspects of these cell transitions are not fully understood. Osteoblasts are true bone-forming cells and differentiate from their pluripotent precursor, the mesenchymal stem cell (MSC); vascular cells that acquire the ability to calcify share aspects of the transcriptional programs exhibited by MSCs differentiating into osteoblasts. What is unknown is whether a fully-differentiated vascular cell directly acquires the ability to calcify by the upregulation of osteogenic genes or, whether these vascular cells first de-differentiate into an MSC-like state before obtaining a "second hit" that induces them to re-differentiate down an osteogenic lineage. Addressing these questions will enable progress in preventative and regenerative medicine strategies to combat vascular calcification pathologies. In this review, we will summarize what is known about the phenotypic switching of vascular endothelial, smooth muscle, and valvular cells.

Keywords: cell phenotype transition; endothelial cell; valve interstitial cell; valvular calcification; vascular calcification; vascular smooth muscle cell.

Figure 1

(A) Three possibilities are operative in ectopic calcification pathogenesis: healthy cells can directly acquire an osteogenic phenotype; there is a step-wise progression where cells transition through a progenitor-like state before acquiring an osteogenic phenotype; healthy cells de-differentiate into progenitor-like cells and are able to stay in this pluripotent state for some time, followed by a cue inducing them re-differentiate back to their initial state or transdifferentiate into calcifying cells. (B) Coinciding with these three possibilities, it is unknown whether these phenotypic transitions are regulated at the transcriptional level of osteogenic genes or whether there are more global epigenetic changes that alter the cell at a more global level