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.

Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways

“…Furthermore, cardiac calcification at the mitral annulus is a process possessing characteristics of both atherosclerotic plaque calcification and media calcification [ 13 ]. In general, the process of arterial calcification has three important pathological characteristics (i) loss of circulating calcification inhibitors (i.e., pyrophosphate (PP i ), (vitamin K-dependent) carboxylated matrix gla protein and fetuin-A) [ 14 , 15 ], (ii) gain of circulating calcification stimulators (i.e., hyperphosphatemia, hypercalcemia and uremic toxins) [ 15 , 16 ] and (iii) the ability of vascular cells, i.e., vascular smooth muscle cells (VSMCs) in the (medial or intimal) arterial wall or valve interstitial cells (VICs) in aortic valves, to transdifferentiate into bone-like cells which goes along with upregulation of osteo/chondrogenic marker genes such as Runt-related transcription factor 2 (Runx2), tissue non-specific alkaline phosphatase (TNAP), Bone morphogenetic protein 2 (BMP2) and SRY-Box transcription factor 9 (Sox9). These bone-like cells produce and release calcified matrix vesicles, in which calcium and phosphate is built up, into the extracellular matrix resulting into mineralization of the surrounding tissue [ 15 , 16 ].…”

Molecular aspects of the pathological activation and differentiation of valvular interstitial cells during the development of calcific aortic stenosis

“…Впрочем, в толще матрикса могут встречаться единичные клетки, ко-экспрессирующие эндотелиальные и мезенхимальные маркеры, например, CD31 и α-SMA [9]. Природа этого явления не до конца понятна, предполагается, что оно может быть связано с эндотелиально-мезенхимальной трансформацией ЭК [9][10][11].…”

Placental Vascular Calcification and Cardiovascular Health: It Is Time to Determine How Much of Maternal and Offspring Health Is Written in Stone

“…Molecular vascular calcification mechanisms are a complex intersection of regulatory pathways, including adenosine signaling, osteochondrogenesis, inflammation, endocrine pathways, hypoxia, malnutrition, autophagy, phosphate transport, and phosphate signaling. Please see these recent reviews for current detail on cardiovascular calcification mechanisms (Wu et al, 2013 ; Hortells et al, 2018 ; Zazzeroni et al, 2018 ).…”