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Journal ArticleDOI

Vascular calcification: an update on mechanisms and challenges in treatment.

01 Mar 2013-Calcified Tissue International (Springer US)-Vol. 93, Iss: 4, pp 365-373
TL;DR: The mechanisms of vascular calcification are reviewed including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts, and microRNAs, and potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcifying are reviewed.
Abstract: Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high-risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a nonocclusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts, and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification are also reviewed.

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Citations
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Journal ArticleDOI
TL;DR: The current state of knowledge about the pathology, molecular biology, and nosology of VCm is reviewed, potential mechanisms responsible for poor prognosis are expanded on, and some of the directions for future research in this area are exposed.
Abstract: Vascular calcifications (VCs) are actively regulated biological processes associated with crystallization of hydroxyapatite in the extracellular matrix and in cells of the media (VCm) or intima (VCi) of the arterial wall. Both patterns of VC often coincide and occur in patients with type II diabetes, chronic kidney disease, and other less frequent disorders; VCs are also typical in senile degeneration. In this article, we review the current state of knowledge about the pathology, molecular biology, and nosology of VCm, expand on potential mechanisms responsible for poor prognosis, and expose some of the directions for future research in this area.

540 citations


Cites background from "Vascular calcification: an update o..."

  • ...expression of bone-related genes is the cause or the consequence of the calcification process(59) is critical, as therapies will differ depending on which mechanism is the initiating process.(3,5)...

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Journal ArticleDOI
TL;DR: Current concepts of central pressure and tensile pulsatile circumferential stress as key mechanical determinants of arterial wall remodeling, cell-ECM interactions depending mainly on the architecture of cytoskeletal proteins and focal adhesion, the large/small arteries cross-talk that gives rise to target organ damage, and inflammatory pathways leading to calcification or atherosclerosis are summarized.
Abstract: The cushioning function of large arteries encompasses distension during systole and recoil during diastole which transforms pulsatile flow into a steady flow in the microcirculation Arterial stiffness, the inverse of distensibility, has been implicated in various etiologies of chronic common and monogenic cardiovascular diseases and is a major cause of morbidity and mortality globally The first components that contribute to arterial stiffening are extracellular matrix (ECM) proteins that support the mechanical load, while the second important components are vascular smooth muscle cells (VSMCs), which not only regulate actomyosin interactions for contraction but mediate also mechanotransduction in cell-ECM homeostasis Eventually, VSMC plasticity and signaling in both conductance and resistance arteries are highly relevant to the physiology of normal and early vascular aging This review summarizes current concepts of central pressure and tensile pulsatile circumferential stress as key mechanical determinants of arterial wall remodeling, cell-ECM interactions depending mainly on the architecture of cytoskeletal proteins and focal adhesion, the large/small arteries cross-talk that gives rise to target organ damage, and inflammatory pathways leading to calcification or atherosclerosis We further speculate on the contribution of cellular stiffness along the arterial tree to vascular wall stiffness In addition, this review provides the latest advances in the identification of gene variants affecting arterial stiffening Now that important hemodynamic and molecular mechanisms of arterial stiffness have been elucidated, and the complex interplay between ECM, cells, and sensors identified, further research should study their potential to halt or to reverse the development of arterial stiffness

436 citations

Journal ArticleDOI
TL;DR: It is shown that 18F-NaF adsorbs to calcified deposits within plaque with high affinity and is selective and specific, the only currently available clinical imaging platform that can non-invasively detect microcalcification in active unstable atherosclerosis.
Abstract: Vascular calcification is a complex biological process that is a hallmark of atherosclerosis. While macrocalcification confers plaque stability, microcalcification is a key feature of high-risk atheroma and is associated with increased morbidity and mortality. Positron emission tomography and X-ray computed tomography (PET/CT) imaging of atherosclerosis using 18F-sodium fluoride (18F-NaF) has the potential to identify pathologically high-risk nascent microcalcification. However, the precise molecular mechanism of 18F-NaF vascular uptake is still unknown. Here we use electron microscopy, autoradiography, histology and preclinical and clinical PET/CT to analyse 18F-NaF binding. We show that 18F-NaF adsorbs to calcified deposits within plaque with high affinity and is selective and specific. 18F-NaF PET/CT imaging can distinguish between areas of macro- and microcalcification. This is the only currently available clinical imaging platform that can non-invasively detect microcalcification in active unstable atherosclerosis. The use of 18F-NaF may foster new approaches to developing treatments for vascular calcification.

375 citations

Journal ArticleDOI
TL;DR: Mechanisms of SMC plasticity in different stages of native atherosclerotic plaque formation, their potential for monoclonal or oligOClonal expansion, as well as recent findings demonstrating the underestimated deleterious role of SMCs are highlighted.
Abstract: Current knowledge suggests that intimal smooth muscle cells (SMCs) in native atherosclerotic plaque derive mainly from the medial arterial layer. During this process, SMCs undergo complex structural and functional changes giving rise to a broad spectrum of phenotypes. Classically, intimal SMCs are described as dedifferentiated/synthetic SMCs, a phenotype characterized by reduced expression of contractile proteins. Intimal SMCs are considered to have a beneficial role by contributing to the fibrous cap and thereby stabilizing atherosclerotic plaque. However, intimal SMCs can lose their properties to such an extent that they become hard to identify, contribute significantly to the foam cell population, and acquire inflammatory-like cell features. This review highlights mechanisms of SMC plasticity in different stages of native atherosclerotic plaque formation, their potential for monoclonal or oligoclonal expansion, as well as recent findings demonstrating the underestimated deleterious role of SMCs in this disease.

287 citations


Cites background from "Vascular calcification: an update o..."

  • ...osteopontin is transiently up-regulated in rat experimentally-induced intimal thickening, and accumulates in calcified areas of human atheromatous plaque.(30) We identified another protein, S100A4, as a marker of R-SMCs in vitro and of intimal SMCs in both pigs and humans....

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Journal ArticleDOI
TL;DR: A review of the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population is provided in this article, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods.
Abstract: Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.

245 citations

References
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Journal ArticleDOI
TL;DR: It is demonstrated that OPG is a critical regulator of postnatal bone mass and regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.
Abstract: Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation. In this study the physiological role of OPG is investigated by generating OPG-deficient mice. Adolescent and adult OPG-/- mice exhibit a decrease in total bone density characterized by severe trabecular and cortical bone porosity, marked thinning of the parietal bones of the skull, and a high incidence of fractures. These findings demonstrate that OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-deficient mice also exhibit medial calcification of the aorta and renal arteries, suggesting that regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.

2,444 citations


"Vascular calcification: an update o..." refers background in this paper

  • ...OPG appears to be protective against vascular calcification since OPG mice developed spontaneous arterial calcification [16] and depleting OPG in ApoE mice increased atherosclerotic lesion progression and calcification [17]....

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  • ...One study found that OPG knockout mice developed extensive vascular calcification in addition to the expected result of osteoporosis [16]....

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Journal ArticleDOI
13 Nov 1997-Nature
TL;DR: RANK and RANKL seem to be important regulators of interactions between T cells and dendritic cells.
Abstract: Dendritic cells are rare haematopoietic cells that reside in a number of organs and tissues. By capturing, processing and presenting antigens to T cells, dendritic cells are essential for immune surveillance and the regulation of specific immunity. Several members of the tumour necrosis factor receptor (TNFR) superfamily are integral to the regulation of the immune response. These structurally related proteins modulate cellular functions ranging from proliferation and differentiation to inflammation and cell survival or deaths. The functional activity of dendritic cells is greatly increased by signalling through the TNFR family member CD40. Here we report the characterization of RANK (for receptor activator of NF-kappaB), a new member of the TNFR family derived from dendritic cells, and the isolation of a RANK ligand (RANKL) by direct expression screening. RANKL augments the ability of dendritic cells to stimulate naive T-cell proliferation in a mixed lymphocyte reaction, and increases the survival of RANK+ T cells generated with interleukin-4 and transforming growth factor (TGF)-beta. Thus RANK and RANKL seem to be important regulators of interactions between T cells and dendritic cells.

2,306 citations

Journal ArticleDOI
20 Jan 2011-Nature
TL;DR: The wideranging functions of microRNAs in the cardiovascular system have provided new perspectives on disease mechanisms and have revealed intriguing therapeutic targets, as well as diagnostics, for a variety of cardiovascular disorders.
Abstract: First recognized as regulators of development in worms and fruitflies, microRNAs are emerging as pivotal modulators of mammalian cardiovascular development and disease. Individual microRNAs modulate the expression of collections of messenger RNA targets that often have related functions, thereby governing complex biological processes. The wideranging functions of microRNAs in the cardiovascular system have provided new perspectives on disease mechanisms and have revealed intriguing therapeutic targets, as well as diagnostics, for a variety of cardiovascular disorders.

1,102 citations


"Vascular calcification: an update o..." refers background in this paper

  • ...The role of miRNAs in cardiovascular biology is currently under intense investigation, and specific miRNAs have been associated with various cardiovascular disorders, including vascular remodeling, cardiac hypertrophy, heart failure, and post–myocardial infarction remodeling [22]....

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Journal ArticleDOI
TL;DR: In adults with asymptomatic AS, the rate of hemodynamic progression and clinical outcome are predicted by jet velocity, the rates of change inJet velocity, and functional status.
Abstract: Background Only limited data on the rate of hemodynamic progression and predictors of outcome in asymptomatic patients with valvular aortic stenosis (AS) are available. Methods and Results In 123 adults (mean age, 63±16 years) with asymptomatic AS, annual clinical, echocardiographic, and exercise data were obtained prospectively (mean follow-up of 2.5±1.4 years). Aortic jet velocity increased by 0.32±0.34 m/s per year and mean gradient by 7±7 mm Hg per year; valve area decreased by 0.12±0.19 cm2 per year. Kaplan-Meier event-free survival, with end points defined as death (n=8) or aortic valve surgery (n=48), was 93±5% at 1 year, 62±8% at 3 years, and 26±10% at 5 years. Univariate predictors of outcome included baseline jet velocity, mean gradient, valve area, and the rate of increase in jet velocity (all P≤.001) but not age, sex, or cause of AS. Those with an end point had a smaller exercise increase in valve area, blood pressure, and cardiac output and a greater exercise decrease in stroke volume. Multiv...

1,053 citations


"Vascular calcification: an update o..." refers background in this paper

  • ...Valve calcification is also linked to increased risk of cardiac events and mortality even if the patient is asymptomatic [4]....

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Journal ArticleDOI
TL;DR: Heterotopic ossification consisting of mature lamellar bone formation and active bone remodeling is a relatively common and unexpected finding in end-stage valvular heart disease and may be associated with repair of pathological microfractures in calcified cardiac valves.
Abstract: Background—For nearly a century, the mechanical failure of calcified heart valves was attributed to a passive degenerative process. Recently, several case reports described bone formation in surgically excised heart valves and suggested an unexpected process of tissue repair. Methods and Results—We studied the prevalence and pathology of heterotopic ossification in 347 surgically excised heart valves (256 aortic, 91 mitral) in 324 consecutive patients (182 men, 142 women; mean age 68 years) who underwent cardiac valve replacement surgery between 1994 and 1998. The valves were examined microscopically to determine the prevalence and features of bone formation and remodeling. Two hundred eighty-eight valves (83%) had dystrophic calcification. Mature lamellar bone with hematopoietic elements and active bone remodeling were present in 36 valves (13%) with dystrophic calcification. Endochondral bone formation, similar to that seen in normal fracture repair, was identified in 4 valves. Microfractures were prese...

995 citations


"Vascular calcification: an update o..." refers background in this paper

  • ...Osteoclastlike cells that express tartrate-resistant acid phosphatase (TRAP) have been found in calcified vascular lesions in humans but were typically present at very low levels and only at advanced stages of disease [6, 20]....

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  • ...In addition, outright cartilage and bone formation have been identified [6, 7]....

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