Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 7:528-536

David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA 90095-1679, USA.
Nature Reviews Cardiology (Impact Factor: 9.18). 09/2010; 7(9):528-36. DOI: 10.1038/nrcardio.2010.115
Source: PubMed


In the past decade, the prevalence, significance, and regulatory mechanisms of vascular calcification have gained increasing recognition. Over a century ago, pathologists recognized atherosclerotic calcification as a form of extraskeletal ossification. Studies are now identifying the mechanism of this remarkable process as a recapitulation of embryonic endochondral and membranous ossification through phenotypic plasticity of vascular cells that function as adult mesenchymal stem cells. These embryonic developmental programs, involving bone morphogenetic proteins and potent osteochondrogenic transcription factors, are triggered and modulated by a variety of inflammatory, metabolic, and genetic disorders, particularly hyperlipidemia, chronic kidney disease, diabetes, hyperparathyroidism, and osteoporosis. They are also triggered by loss of powerful inhibitors, such as fetuin A, matrix Gla protein, and pyrophosphate, which ordinarily restrict biomineralization to skeletal bone. Teleologically, soft-tissue calcification might serve to create a wall of bone to sequester noxious foci such as chronic infections, parasites, and foreign bodies. This Review focuses on atherosclerotic and medial calcification. The capacity of the vasculature to produce mineral in culture and to produce de novo, vascularized, trabecular bone and cartilage tissue, even in patients with osteoporosis, should intrigue investigators in tissue engineering and regenerative biology.

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Available from: Andrew Sage, Jan 22, 2016
    • "In this study, we found that the pro-inflammatory environment of the atherosclerotic mice did not inhibit the formation of bone in subcutaneous implants but exaggerated the effect leading to more advanced calcification, particularly in the case of VSCs. In the atherosclerotic environment, a number pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β are increased [39] and inflammatory cytokines are strongly related to ectopic bone formation [40]. What triggers the inflammatory reaction in atherosclerosis is not completely understood. "
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    ABSTRACT: The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. VSCs and MSCs isolated from atherosclerotic ApoE(-/-) mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE(-/-) and C57BL/6 mice using a crossover study design. Atherosclerotic ApoE(-/-) MSCs and VSCs formed bone when implanted in C57BL/6 mice. In ApoE(-/-) mice, these cells generated more mature bone than C57BL/6 cells. The atherosclerotic in vivo environment alone promoted bone formation by implanted C57BL/6 cells. Un-primed C57BL/6 VSCs were unable to form bone in either mouse strain. Treatment of ApoE(-/-) VSC chondrogenic cultures with interleukin (IL)-6 resulted in significantly increased glycosaminoglycan deposition and expression of characteristic chondrogenic genes at 21 days. In conclusion, resident vascular cells from atherosclerotic environment respond to the inflammatory milieu and undergo calcification. IL-6 may have a role in aberrant differentiation of VSCs contributing to vascular calcification in atherosclerosis. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Stem Cells
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    • "In particular, the osteogenic transcription factor Runx2 received attention in vascular biology, emerging as a marker of VSMC trans-differentiation towards an osteogenic phenotype, and contributing to the active vascular calcification process[154,157,158]. However, while Runx2 is induced in diabetic aortae via redox-sensitive mechanisms to promote vascular fibrosis (see above), Runx2 overexpression per se is insufficient to induce vascular calcification[147], underlining the complex, multi-factorial nature of calcification processes[149,159]. Finally, a redox-sensitive formation of advanced glycation end-products (AGEs), causing cross-linking of collagen molecules, may lead to loss of collagen elasticity and a subsequent increase in arterial stiffness[160]. "
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    ABSTRACT: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.
    Full-text · Article · Oct 2015 · International Journal of Molecular Sciences
    • "Until that time calcification of soft tissues was considered to be a passive process. Nowadays, evidence is present that vascular calcification is a highly regulated cell-mediated process [93]. Different groups demonstrated in vitro that MGP mRNA levels are upregulated in VSMCs in response to high calcium levels [148, 149]. "
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    ABSTRACT: In the past few decades vitamin K has emerged from a single-function "haemostasis vitamin" to a "multi-function vitamin." The use of vitamin K antagonists (VKA) inevitably showed that the inhibition was not restricted to vitamin K dependent coagulation factors but also synthesis of functional extrahepatic vitamin K dependent proteins (VKDPs), thereby eliciting undesired side effects. Vascular calcification is one of the recently revealed detrimental effects of VKA. The discovery that VKDPs are involved in vascular calcification has propelled our mechanistic understanding of this process and has opened novel avenues for diagnosis and treatment. This review addresses mechanisms of VKDPs and their significance for physiological and pathological calcification.
    No preview · Article · Aug 2014 · Molecular Nutrition & Food Research
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