Regulatory mechanisms in vascular calcification.

David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA 90095-1679, USA.
Nature Reviews Cardiology (Impact Factor: 10.4). 09/2010; 7(9):528-36. DOI: 10.1038/nrcardio.2010.115
Source: PubMed

ABSTRACT 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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    ABSTRACT: Both KLF5 and Runx2 are involved in phenotypic switching of vascular smooth muscle cells (VSMC). However, the potential link between KLF5 and Runx2 in mediating vascular calcification remains unclear. The aim of the study was to elucidate the actual relationship between KLF5 and Runx2 in mediating VSMC calcification. We found that high phosphate increased the expression of KLF5, which is accompanied by loss of SM α-actin and SM22α, as well as gain of Runx2 expression. Overexpression of KLF5 increased, while knockdown of KLF5 decreased, Runx2 expression and calcification. Further study showed that KLF5 bound directly to the Runx2 promoter and activated its transcription. KLF5 was also induced markedly in the calcified aorta of adenine-induced uremic rats. In conclusion, we demonstrate a critical role for KLF5-mediated induction of Runx2 in high phosphate-induced VSMC calcification.
    Bioscience Reports 09/2014; · 2.85 Impact Factor
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    ABSTRACT: The link between vascular calcification (VC) and increased mortality is now well established. Over time, as clinical importance of this phenomenon has begun to be fully considered, scientists have highlighted more and more physiopathological mechanisms and signaling pathways that underlie VC. Several conditions such as diabetes, dyslipidemia and renal diseases are undoubtelly identified as predisposing factors. But even if the process is better understood, many questions still remain unanswered. This review briefly develops the various theories that attempt to explain mineralization genesis. Nonetheless, the main purpose of the article is to provide a profile of the various existing biomarkers of VC. Indeed, in the past years, a lot of inhibitors and promoters, which form a dense and interconnected network, were identified. Given importance to assess and control mineralization process, a focusing on accumulated knowledge of each marker seemed to be necessary. Therefore, we tried to define their respective role in the physiopathology and how they can contribute to calcification risk assessment. Among these, Klotho / fibroblast growth factor-23, fetuin-A, Matrix Gla protein, Bone morphogenetic protein-2, osteoprotegerin, osteopontin, osteonectin, osteocalcin, pyrophosphate and sclerostin are specifically discussed.
    Clinica Chimica Acta 09/2014; 438. · 2.76 Impact Factor
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    ABSTRACT: Nowadays, vascular calcification is considered as an actively regulated and complex process that remains not completely understood.•A large variety of conditions can modulate vascular microenvironment composition, such as bone turnover, inflammation, vitamin D status or even oxidative stress.•Inhibitors and promoters of vascular calcification form a dense and interconnected network.•It is essential to define the role of each biomarker in the physiopathology and to determine how they can contribute to calcification risk assessment.
    Clinica Chimica Acta. 01/2015; 438.


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