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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    • "VC is caused by a failure to maintain homeostasis of the vasculature in diseases like atherosclerosis, diabetes, chronic kidney disease (CKD), and during normal aging [1-3]. Inflammation, reactive oxygen species, and hyperlipidemia are major contributors to the pathogenesis of VC [4-7]. Interestingly, a number of studies have shown VC recapitulates embryonic osteogenesis, and that vascular smooth muscle cells (VSMCs) are able to transdifferentiate into both osteogenic and chondrogenic cells [1,8,9]. "
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    ABSTRACT: The transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells has been implicated in the context of vascular calcification. We investigated the roles of vitamin D receptor (Vdr) and runt-related transcription factor 2 (Runx2) in the osteoblastic differentiation of VSMCs in response to vitamin D3 using in vitro VSMCs cultures and in vivo in Vdr knockout (Vdr (-/-) ) and Runx2 carboxy-terminus truncated heterozygous (Runx2 (+/ΔC) ) mice. Treatment of VSMCs with active vitamin D3 promoted matrix mineral deposition, and increased the expressions of Vdr, Runx2, and of osteoblastic genes but decreased the expression of smooth muscle myosin heavy chain in primary VSMCs cultures. Immunoprecipitation experiments suggested an interaction between Vdr and Runx2. Furthermore, silencing Vdr or Runx2 attenuated the procalcific effects of vitamin D3. Functional cooperation between Vdr and Runx2 in vascular calcification was also confirmed in in vivo mouse models. Vascular calcification induced by high-dose vitamin D3 was completely inhibited in Vdr (-/-) or Runx2 (+/ΔC) mice, despite elevated levels of serum calcium or alkaline phosphatase. Collectively, these findings suggest that functional cooperation between Vdr and Runx2 is necessary for vascular calcification in response to vitamin D3.
    PLoS ONE 12/2013; 8(12):e83584. DOI:10.1371/journal.pone.0083584 · 3.23 Impact Factor
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    • "CKD fosters pro-atherogenic conditions through multiple pathways, including oxidative stress, increased infection and inflammation, decreased clearance of inflammatory mediators, increased formation and decreased clearance of AGEs, LDL oxidation, and adverse changes in endothelial and vascular smooth muscle cells [Stenvinkel et al. 2003]. Atherogenesis and inflammation, not only phosphate–calcium metabolism, in turn contribute to vascular calcification [Sage et al. 2010]. Sevelamer thus may ameliorate multiple processes that contribute to calcification and other sources of cardiovascular disease risk in CKD (Figure 5). "
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    ABSTRACT: Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3-5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2-4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent INDEPENDENT-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, INDEPENDENT-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.
    Therapeutic Advances in Cardiovascular Disease 12/2013; 7(6):322-42. DOI:10.1177/1753944713513061 · 2.13 Impact Factor
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    • "MGP-null arterial disease has been described primarily as a product of chondrogenic transformation of Mgp-/- VSM resulting in the ectopic formation of cartilage in the vessel wall, extensive calcification, and ultimately rupture of the blood vessels soon after birth [21]. While mechanisms underlying the osteogenic transformation of VSM induced by warfarin [10–13] and by hyperphosphatemia [22,23] are emerging [7,24,25], the chondrogenic transformation of vascular cells that is prominent in uremia- and diabetes-associated medial calcification [26,27] is not well understood. The Mgp-/- vasculature is an excellent model for mechanistic analysis of chondrogenic transformation in VSM because 97% of the chondrocyte-like cells in arterial cartilaginous metaplasia originate from VSM [13] suggesting a minimal (if any) contribution by circulating or resident multipotent mesenchymal progenitors. "
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    ABSTRACT: Cartilaginous metaplasia of vascular smooth muscle (VSM) is characteristic for arterial calcification in diabetes and uremia and in the background of genetic alterations in matrix Gla protein (MGP). A better understanding of the molecular details of this process is critical for the development of novel therapeutic approaches to VSM transformation and arterial calcification. This study aimed to identify the effects of bioflavonoid quercetin on chondrogenic transformation and calcification of VSM in the MGP-null mouse model and upon TGF-β3 stimulation in vitro, and to characterize the associated alterations in cell signaling. Molecular analysis revealed activation of β-catenin signaling in cartilaginous metaplasia in Mgp-/- aortae in vivo and during chondrogenic transformation of VSMCs in vitro. Quercetin intercepted chondrogenic transformation of VSM and blocked activation of β-catenin both in vivo and in vitro. Although dietary quercetin drastically attenuated calcifying cartilaginous metaplasia in Mgp-/- animals, approximately one-half of total vascular calcium mineral remained as depositions along elastic lamellae. Quercetin is potent in preventing VSM chondrogenic transformation caused by diverse stimuli. Combined with the demonstrated efficiency of dietary quercetin in preventing ectopic chondrogenesis in the MGP-null vasculature, these findings indicate a potentially broad therapeutic applicability of this safe for human consumption bioflavonoid in the therapy of cardiovascular conditions linked to cartilaginous metaplasia of VSM. Elastocalcinosis is a major component of MGP-null vascular disease and is controlled by a mechanism different from chondrogenic transformation of VSM and not sensitive to quercetin.
    PLoS ONE 09/2013; 8(9):e76210. DOI:10.1371/journal.pone.0076210 · 3.23 Impact Factor
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