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
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.
Figures in this publication
Get notified about updates to this publicationFollow publication
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
[Show abstract] [Hide abstract] 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.
- "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  and inflammatory cytokines are strongly related to ectopic bone formation . What triggers the inflammatory reaction in atherosclerosis is not completely understood. "
[Show abstract] [Hide abstract] ABSTRACT: Vascular calcification (VC), a disorder that causes blood vessel hardening and dysfunction, is a significant risk factor for type-2 diabetes mellitus (T2DM), which invariably manifests associated cardiovascular complications. Although the clinical effects of VC have been well-documented, the precise cellular events underlying the manifestation and progression of VC are only now coming to light. Current research models indicate that VC likely involves signalling pathways traditionally associated with bone remodelling, such as the OPG/RANKL/TRAIL signalling system. In this respect, receptor activator of NF-κB ligand (RANKL) promotes VC whilst osteoprotegerin (OPG) acts as a RANKL decoy receptor to block this effect, events that contrast with the known functional influence of these proteins during bone metabolism. Moreover, evidence suggests that tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), an alternative decoy ligand for OPG, may exert an anti-calcific influence within the vasculature. In the current review, we conduct a timely examination of this complex VC pathology from both mechanistic and therapeutic perspectives. Our objectives are twofold: (i) to critically assess our current understanding of both osteogenic and vascular calcification pathways, with particular focus on the co-interactive roles of OPG, RANKL, and TRAIL. Extensive in vitro, in vivo, and clinical studies will therefore be reviewed and critical findings highlighted; and (ii) to examine a range of therapeutic approaches of potential relevance to VC pathology. In this regard, a clear focus on VC as it applies to T2DM and cardiovascular disease (and particularly atherosclerosis) will be maintained.
- "Importantly, all three glycoproteins have been identified within vascular tissues, circulating blood, and calcified atherosclerotic lesions [44,74], with clinical observations supporting a likely role for these regulatory proteins in the VC process in patients with T2DM and CVD. In our view, careful analysis of these protein targets within a clinical setting (addressed below) may unlock their potential value to CVD and T2DM with respect to risk assessment and disease management [40,75]: "
[Show abstract] [Hide abstract] 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.
- "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, 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. "