(Circulation. 1999;100:2168.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Medial Localization of Mineralization-Regulating Proteins in Association With Mönckeberg’s Sclerosis
Evidence for Smooth Muscle Cell–Mediated Vascular Calcification
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and published in abstract form (Circulation. 1997:96[suppl I]:I-666).
From the Department of Medicine, Addenbrooke’s Hospital (C.M.S., D.P., P.L.W.), Cambridge, UK; Papworth Hospital (N.R.B.C.), Papworth-Everard, Cambridgeshire, UK; and the Diabetic Clinic (M.E.E.) and Pathology (J.R.S.), Kings College Hospital, Camberwell, London, UK.
Correspondence to Dr C.M. Shanahan, Department of Medicine, A.C.C.I., Level 6, Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail cs131{at}mole.bio.cam.ac.uk
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Abstract |
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Background—Calcification of the media of peripheral arteries is referred to as Mönckeberg’s sclerosis (MS) and occurs commonly in aged and diabetic individuals. Its pathogenesis is unknown, but its presence predicts risk of cardiovascular events and leg amputation in diabetic patients. Several studies have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascular calcification may be a regulated process with similarities to developmental osteogenesis. Therefore, we examined gene expression in vessels with MS to determine whether there was evidence for a regulated calcification process in the vessel media.
Methods and Results—In situ hybridization, immunohistochemistry,
and semiquantitative reverse-transcription polymerase chain reaction
were used to examine the expression of mineralization-regulating
proteins in human peripheral arteries with and without MS.
MS occurred in direct apposition to medial vascular smooth muscle cells
(VSMCs) in the absence of macrophages or lipid. These VSMCs
expressed the smooth muscle–specific gene SM22
and high levels of
matrix Gla protein but little osteopontin mRNA. Compared with normal
vessels, vessels with MS globally expressed lower levels of matrix Gla
protein and osteonectin, whereas alkaline phosphatase, bone
sialoprotein, bone Gla protein, and collagen II, all indicators of
osteogenesis/chondrogenesis, were upregulated. Furthermore, VSMCs
derived from MS lesions exhibited osteoblastic properties and
mineralized in vitro.
Conclusions—These data indicate that medial calcification in MS lesions is an active process potentially orchestrated by phenotypically modified VSMCs.
Key Words: osteopontin • proteins • cartilage • muscle, smooth • diabetes mellitus
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Vascular calcification is associated with increased risk of myocardial infarction, limb amputation, and morbidity after vascular surgery.1 2 3 4 5 It occurs at 2 anatomic sites: in the intima, where it is invariably associated with atherosclerosis, and in the tunica media.6 In atherosclerosis, intimal macrophages and vascular smooth muscle cells (VSMCs) express collagenous (collagen types I and IV) and noncollagenous bone matrix proteins (osteopontin [OP], osteonectin [SPARC; secreted protein, acidic, rich in cysteine], matrix Gla protein [MGP], osteoglycin, and bone morphogenetic protein [BMP 2]), often in association with calcification.7 8 9 10 11 The association of intimal calcification with lipid, apoptotic cells, and matrix vesicles, important elements in bone development, suggests that intimal calcification is an active rather than a degenerative process, although the precise mechanism by which calcification is induced is poorly understood.4 12 13 14 15 16 17
Human medial calcification, Mönckeberg’s sclerosis (MS), is common and occurs independently of atherosclerosis, implying different etiological mechanisms.6 18 MS was originally described in aged males (>50 years); however, it is most commonly seen in diabetic individuals.19 20 The clinical significance of MS remains controversial; however, it is as an independent predictor of cardiovascular events in diabetic patients and is associated with trophic foot ulceration and peripheral artery occlusive disease.5 21 22 23
MGP is a 10-kDa circulating protein that contains 5 
-carboxyglutamic
acid residues that bind calcium in soft tissues.16 24 Mice
lacking MGP develop extensive medial calcification and cartilaginous
metaplasia, resulting in neonatal death by aortic rupture. We have
previously shown that MGP is expressed by normal human medial VSMCs and
is upregulated in the calcified atherosclerotic intima. However, its
role in medial calcification in humans has not been
elucidated.8 We hypothesized that medial calcification is
a regulated process, and we determined the cellular pattern of
expression of mineralization-regulating proteins in human MS lesions.
Our findings suggest that in association with MS, medial VSMCs become
modified and exhibit osteocytic/chondrocytic changes in gene
expression, potentially conferring mineralization-regulating properties
on them.
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Methods |
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In Situ Hybridization
Peripheral arteries from patients undergoing leg amputation (see Table
) were snap-frozen
and mounted in Tissue-Tek OCT embedding compound (Miles Ames Division,
Inc). Sections (8 to 10 µm) were mounted onto gelatinized slides
and processed for in situ hybridization as described
previously.8 11 Human OP and MGP probes were transcribed
from full-length cDNA clones of 1.4 and 0.7 kb, respectively (ATCC/NIH
repository, Rockville, Md), whereas rat SM22 (3RF10) was from a
1.0-kb cDNA clone.8 11 Slides were exposed for 3 to 6
weeks, developed, stained with hematoxylin and eosin, and mounted.
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Immunohistochemistry
Immunohistochemistry was performed with a Dako avidin-biotin
immunoperoxidase kit according to the manufacturer’s instructions.
VSMCs were identified with a mouse monoclonal antibody (Dako, M815,
dilution 1:25) to human -smooth muscle (-SM) actin, and
macrophages were identified with a mouse monoclonal antibody to
CD68 (Dako, macrophage EMB11, dilution 1:20). A mouse
monoclonal OP antibody (MPIIIB101) was obtained
from the National Institute of Child Development Hybridoma Bank (Iowa
City, IA) and diluted 1:200.8 The MGP polyclonal antibody
(a gift from Dr R.F. Loeser, The Bowman Gray School of Medicine, Wake
Forest University, Raleigh, NC) was raised in rabbits immunized with a
19-amino-acid synthetic peptide to a bovine MGP sequence as
described25 and diluted 1:100. Controls were performed
with the primary antibody substituted with either PBS or an irrelevant
antibody. Calcium was demonstrated with von Kossa stain and lipid by
oil red O staining.
Culture of Human VSMCs
Explants were cultured from peripheral arteries of 5
diabetic patients with MS and 5 control subjects (men and women aged 48
to 93 years). A piece of each vessel was retained for subsequent
pathological examination. The endothelial and
adventitial layers were removed, and medial smooth muscle cells
directly in contact with calcified regions or calcium deposits alone
were placed in 6-well plates with M199 media containing 20% fetal calf
serum and antibiotic supplements. Six to 12 isolates were established
from each vessel. Cell growth began after 
2 weeks, and at
confluence, RNA was harvested from each well and cDNA prepared from 5
µg of total RNA. Wells left to become postconfluent were stained with
von Kossa stain after 30 days.26
Reverse-Transcription Polymerase Chain Reaction Analysis of
Gene Expression in Human Arteries and Cultured Cells
mRNA was extracted from cultured cells or from 20 frozen
sections cut from each vessel by lysis in buffer containing NP40, as
previously described.11 A section was cut before and after
the 20 sections for reverse-transcription polymerase chain reaction
(RT-PCR) for pathological analysis. The RNA pellet was
suspended in water and treated with DNase (1 hour at 37°C with 10 U
of RNase-free DNase). Total RNA was reverse-transcribed for 1 hour at
42°C with avian myeloblastosis virus (AMV) reverse transcriptase and
oligo-dT primer. To ensure that each PCR reaction was performed within
the linear range of amplification, test reactions were performed for
each primer pair at 20, 25, 30, 35, and 40 cycles. Southern blots were
done on these reaction products, and they were hybridized and
counted; plots of these results were used to establish linearity.
Subsequently, 2.5 µL of cDNA was used in each 20-µL PCR reaction
cycled for 30 to 35 cycles at 94°C for 2 minutes, annealing
temperature for 1.5 minutes, and extension for 2 minutes at
72°C. Primers were designed from published human sequences in
the Genbank/European Molecular Biology Laboratory databases, with the
size of the PCR amplification product verifying that only cDNA was
amplified. PCR products were sequenced or hybridized to a known
cDNA. Reactions were performed twice, and positive (cDNA from human
bone sections or SaOS cells) and negative (no cDNA) controls were
included. PCR products were run on a 1% agarose gel, subjected to
Southern blotting, and hybridized with appropriate
32P-labeled probes, then washed at high
stringency. Quantification was performed by real-time counting on an
Instant-Imager (Packard), and results were standardized to a
ß-microglobulin control.
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Results |
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Cellular Composition and Calcium and Lipid Accumulation in MS Lesions
Peripheral arteries from consecutive amputations were taken from patients undergoing surgery because of gangrene in the lower limb (diabetic patients) or for ischemia related to atherosclerosis or trauma (nondiabetic patients) (Table
). All diabetic patients exhibited extensive medial
calcification, whereas only 1 older nondiabetic patient exhibited such
calcification. In mildly affected arteries, medial calcification,
associated with elastic fibers, was present throughout most of the
medial width. In advanced lesions, the media was filled with
circumferential rings of calcium, and at later stages, osteocytes were
seen within bone trabeculae with apparent bone marrow
formation (Figure 1).
Calcification in the media occurred in the absence of
macrophages and lipid. This contrasted with the scattered,
globular calcification of the intima, which was invariably associated
with lipid and macrophages (Figures 1 and 2). Medial calcification was found in
association with -SM actin–positive VSMCs, and significantly,
calcium deposits were also present within apparently normal areas
of VSMCs deep in the media (Figure 2). Moreover, these VSMCs
expressed high levels of SM22 (Figure 3).
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Gene Expression and Protein Distribution of MGP and OP in
Arteries
MGP mRNA was detected throughout the media of normal arteries, but
expression was low in the media of arteries with MS. However, in a
small subset of VSMCs adjacent to medial calcification, MGP mRNA
expression was highly elevated (Figure 3). MGP protein was
present in the media of most arteries in a striated pattern, which
suggests it was associated with the elastic lamina. However, in
arteries with severe MS, this pattern was lost, and deposition was more
diffuse and patchy (Figure 4).
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High expression of OP mRNA was only detected in a subset of
macrophages in atherosclerotic lesions (Figure 3). In
normal vessels, OP protein was not detectable in the media, but it
accumulated in MS lesions at the smooth muscle cell–calcium interface
(Figure 2). OP protein surrounded all areas of calcification,
including ossified regions of the media (not shown).
RT-PCR Analysis of Bone-Associated Gene Expression in
Arteries With and Without MS
The above analyses indicated that medial calcification and
ossification were closely associated with VSMCs. To evaluate the
phenotype of VSMCs within MS lesions, semiquantitative RT-PCR
analysis of cDNA derived from tissue sections was performed
with sections of arteries devoid of
atherosclerosis.
Expression of SM22, OP, and BMP2 was detectable in both MS and
normal vessels. However, despite the high levels of MGP mRNA expressed
by a subset of VSMCs, overall, MGP mRNA expression was lower in vessels
with MS than in normal vessels (Figure 5). Normal vessels expressed undetectable
to low levels of alkaline phosphatase (ALK), bone sialoprotein (BSP),
and bone Gla protein (BGP). In contrast, arteries with MS expressed
significantly higher levels of mRNA for all 3 proteins (Figure 5). The level of expression of these genes did not correlate
with the degree of calcification. In situ hybridization confirmed that
expression of mRNA for these 3 proteins in MS lesions was at a low
level throughout the vessel media (not shown). VSMCs in normal arteries
express SPARC at high levels and collagen (COL) II, a differentiation
marker for chondrocytes, at low levels. However, in MS arteries, there
was a significant reduction in the level of SPARC expression and a
significant increase in COL II expression. In contrast, there were no
differences in expression of COL I, which was variably expressed
(Figure 5).
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Primary Culture of MS-Derived VSMCs
Primary explant cultures of VSMCs were established to examine
whether VSMCs derived from MS vessels could mineralize in vitro. RT-PCR
was used to determine the extent of bone-associated gene expression in
confluent, primary cell cultures from isolates of VSMCs derived from
both normal and MS vessels. Gene expression in these VSMCs was compared
with that of SaOS-2 cells, an osteoblast-like cell line.
At confluence, all primary cell explant cultures showed a
"hills-and-valleys" morphology, were -SM actin positive, and
expressed SM22 (Figure 6A). In
monolayer culture, these cell isolates expressed MGP, COL I, COL II,
and SPARC at generally much higher levels than in SaOS-2 cells. They
also expressed ALK, BGP, OP, and BMP2, some at higher levels than in
SaOS-2 cells. Only BSP was expressed at lower levels by VSMCs derived
from MS vessels compared with both VSMCs derived from normal vessels
and SaOS-2 cells (Figure 6C). After confluence, all VSMC
isolates formed multicellular, nodular condensations that mineralized
after 30 days (Figure 6B). Moreover, isolates of each culture
maintained these properties after multiple passages (not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Medial calcification is almost exclusively associated with VSMCs in contrast to intimal calcification, which occurs in macrophage- and lipid-rich atherosclerotic lesions. We have found that in MS, VSMC expression of MGP and SPARC is diminished, whereas expression of ALK, BSP, BGP, and COL II is increased. This osteocytic/chondrocytic transformation of VSMCs suggests that medial calcification is a regulated process that reflects either an adaptive response to limit mineralization or an osteogenic response to facilitate it.
What Is the Role of Mineralization-Regulating Proteins in the
Vasculature?
Although evidence from the MGP knockout mouse suggests that medial
calcification in the developing artery is actively inhibited by
MGP,24 its role in adult human vessels is unknown. Total
expression of MGP was lower in vessels with MS, which suggests that
reduced MGP may predispose to calcification. Its localized upregulation
by VSMCs in MS lesions may reflect an attempt to enhance calcium
clearance. In support of this concept, we have shown that when human
VSMCs calcify in vitro, MGP mRNA expression is upregulated at precisely
the time hydroxyapatite is first detected.26 Calcification
in the presence of MGP suggests that production may be
"swamped" or that the MGP/Ca complex is unable to escape from the
vessel wall, leading to accumulation of MGP protein.8
Alternatively, it is possible that in MS patients, MGP may be
dysfunctional, because the levels of -carboxylase and its essential
cofactor, vitamin K, are reduced in vessels with age.27
More studies are required to elucidate the precise role of MGP in human
vascular calcification.
Expression of OP, an RGD-containing phosphoprotein that can bind calcium and mediate cell adhesion and migration, was high in macrophages in calcified atherosclerotic lesions but low in human medial VSMCs in normal and MS vessels.28 In a previous study,26 we showed that OP is not highly expressed by calcifying VSMCs in vitro; therefore, it is unlikely that OP promotes vascular calcification. Osteopontin is a powerful inhibitor of hydroxyapatite crystal formation in vitro.28 In the present study, despite low mRNA expression, the protein accumulated at the VSMC/calcification interface in a distribution pattern similar to that observed in bone and dentine, in which OP is thought to regulate the rate of mineralization and cement cellular and mineral junctions.29 The expression of OP by normal medial VSMCs and its accumulation in association with calcification suggest that OP may have a specific role as an inhibitor of calcification in the normal vasculature.
Expression of ALK, BSP, and BGP was significantly higher in MS than in normal vessels. ALK, an early marker of osteogenesis, is thought to promote mineralization by providing a source of orthophosphate for incorporation into CaPO4 mineral.30 The function of BSP is less clearly defined, although in vitro evidence suggests it may be involved in the nucleation of hydroxyapatite at the mineralization front of bone.31 However, BSP also has an RGD-domain, which suggests that, like osteopontin, it may have roles in regulating mineralization and in promoting cell adhesion and migration.32 BGP, like MGP, contains calcium-binding Gla residues that can inhibit hydroxyapatite crystal growth in vitro.33 Mice lacking a functional BGP gene develop bones of higher density than normal, which suggests BGP is also a negative regulator of bone formation in vivo.34 However, the expression of BSP and BGP is not restricted to bone; both are expressed in soft tissues prone to calcification, which suggests that under specific conditions, they may be expressed by diverse cell types to regulate ectopic calcification.32 35
SPARC is an abundant matrix protein in bone, where it links collagen and mineral, whereas in vitro, it is one of the most potent inhibitors of hydroxyapatite crystal formation.30 36 The high expression of SPARC in the normal vasculature and its absence in MS lesions suggest that its loss may promote mineralization. In contrast, COL II was expressed at low levels in the normal vasculature but upregulated in MS lesions. COL II has been implicated in the regulation of mineralization, because it can bind annexin V, which is essential for matrix vesicle function.30 This is the first report of COL II expression in the human vasculature, and its association with medial calcification may be analogous to the "cartilaginous metaplasia" described in the MGP knockout mouse.
Are VSMCs Responsible for the Formation of Bone in MS?
BMP2 has previously been found in intimal calcification and can
induce ectopic bone formation.10 37 However, its
expression in both normal and MS vessels suggests it is unlikely to
induce medial ossification. In MS lesions, there were no chondrocytes
or osteoblasts, and the cells associated with calcification and bone
were positive for -SM actin and SM22 and therefore were likely to
be VSMCs. Significantly, we found that noncloned, unpassaged human
VSMCs exhibited an osteoblastic gene expression profile before they
formed nodules and accumulated hydroxyapatite. Furthermore, this
phenotype was common to VSMCs derived from normal vessels and
MS lesions. Thus, VSMCs in vitro and in vivo can coexpress osteoblastic
and VSMC-specific genes. However, it is unclear whether VSMCs can
orchestrate bone formation, and it cannot be ruled out that other
locally recruited cells, such as pericytes, or circulating cells with
the potential to differentiate into osteoblasts may be responsible for
the initiation of bone in MS lesions.38
Conclusions
The above observations imply MS is due to a regulated
calcification process and that constitutive expression of MGP, OP, and
SPARC in normal vessels inhibits calcification. However, in the
presence of calcification, VSMCs express a number of
osteocytic/chondrocytic markers that act to either facilitate or
regulate the calcification process. The signals that initiate
expression of osteocytic/chondrocytic proteins in human VSMCs remain to
be determined. The spontaneous adoption of an osteocytic/chondrocytic
phenotype by human VSMCs in culture may provide a model to test
putative regulatory factors and potential therapeutic interventions to
prevent vascular calcification.
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Acknowledgments |
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Support for this work was by British Heart Foundation grants to Dr Shanahan (BHF Basic Scientist Lecturer) and Dr Weissberg (BHF Professor of Cardiovascular Medicine).
Received April 21, 1999; revision received July 2, 1999; accepted July 15, 1999.
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M. Y. Speer, H.-Y. Yang, T. Brabb, E. Leaf, A. Look, W.-L. Lin, A. Frutkin, D. Dichek, and C. M. Giachelli Smooth Muscle Cells Give Rise to Osteochondrogenic Precursors and Chondrocytes in Calcifying Arteries Circ. Res., March 27, 2009; 104(6): 733 - 741. [Abstract] [Full Text] [PDF]
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P. J. Matias, C. Ferreira, C. Jorge, M. Borges, I. Aires, T. Amaral, C. Gil, J. Cortez, and A. Ferreira 25-Hydroxyvitamin D3, arterial calcifications and cardiovascular risk markers in haemodialysis patients Nephrol. Dial. Transplant., February 1, 2009; 24(2): 611 - 618. [Abstract] [Full Text] [PDF]
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 J. Atkinson Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences J Appl Physiol, November 1, 2008; 105(5): 1643 - 1651. [Abstract] [Full Text] [PDF]
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 P. A. McCullough, V. Agrawal, E. Danielewicz, and G. S. Abela Accelerated Atherosclerotic Calcification and Monckeberg's Sclerosis: A Continuum of Advanced Vascular Pathology in Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., November 1, 2008; 3(6): 1585 - 1598. [Abstract] [Full Text] [PDF]
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 M. J. Duer, T. Friscic, D. Proudfoot, D. G. Reid, M. Schoppet, C. M. Shanahan, J. N. Skepper, and E. R. Wise Mineral Surface in Calcified Plaque Is Like That of Bone: Further Evidence for Regulated Mineralization Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 2030 - 2034. [Abstract] [Full Text] [PDF]
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 R. C. Shroff, R. McNair, N. Figg, J. N. Skepper, L. Schurgers, A. Gupta, M. Hiorns, A. E. Donald, J. Deanfield, L. Rees, et al. Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis Circulation, October 21, 2008; 118(17): 1748 - 1757. [Abstract] [Full Text] [PDF]
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 A. Fales-Williams, B. Sponseller, and H. Flaherty Idiopathic arterial medial calcification of the thoracic arteries in an adult horse J Vet Diagn Invest, September 1, 2008; 20(5): 692 - 697. [Abstract] [Full Text] [PDF]
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 L. G. Arroyo, M. A. Hayes, J. DeLay, C. Rao, B. Duncan, and L. Viel Arterial Calcification in Race Horses Vet. Pathol., September 1, 2008; 45(5): 617 - 625. [Abstract] [Full Text] [PDF]
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C. Bouvet, S. Moreau, J. Blanchette, D. de Blois, and P. Moreau Sequential Activation of Matrix Metalloproteinase 9 and Transforming Growth Factor {beta} in Arterial Elastocalcinosis Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 856 - 862. [Abstract] [Full Text] [PDF]
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S. Morony, Y. Tintut, Z. Zhang, R. C. Cattley, G. Van, D. Dwyer, M. Stolina, P. J. Kostenuik, and L. L. Demer Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr( / ) Mice Circulation, January 22, 2008; 117(3): 411 - 420. [Abstract] [Full Text] [PDF]
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O. Phan, O. Ivanovski, I. G. Nikolov, N. Joki, J. Maizel, L. Louvet, M. Chasseraud, T. Nguyen-Khoa, B. Lacour, T. B. Drueke, et al. Effect of oral calcium carbonate on aortic calcification in apolipoprotein E-deficient (apoE-/-) mice with chronic renal failure Nephrol. Dial. Transplant., January 1, 2008; 23(1): 82 - 90. [Abstract] [Full Text] [PDF]
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 J. Cunningham, J. Floege, G. London, M. Rodriguez, and C. M. Shanahan Clinical Outcomes in Secondary Hyperparathyroidism and the Potential Role of Calcimimetics NDT Plus, January 1, 2008; 1(suppl_1): i29 - i35. [Abstract] [Full Text] [PDF]
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 J. R. Wu-Wong, M. Nakane, J. Ma, X. Ruan, and P. E. Kroeger Elevated phosphorus modulates vitamin D receptor-mediated gene expression in human vascular smooth muscle cells Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1592 - F1604. [Abstract] [Full Text] [PDF]
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G. Molostvov, S. James, S. Fletcher, J. Bennett, H. Lehnert, R. Bland, and D. Zehnder Extracellular calcium-sensing receptor is functionally expressed in human artery Am J Physiol Renal Physiol, September 1, 2007; 293(3): F946 - F955. [Abstract] [Full Text] [PDF]
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R. Westenfeld, C. Schafer, R. Smeets, V. M. Brandenburg, J. Floege, M. Ketteler, and W. Jahnen-Dechent Fetuin-A (AHSG) prevents extraosseous calcification induced by uraemia and phosphate challenge in mice Nephrol. Dial. Transplant., June 1, 2007; 22(6): 1537 - 1546. [Abstract] [Full Text] [PDF]
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 C. Bouvet, W. Peeters, S. Moreau, D. deBlois, and P. Moreau A new rat model of diabetic macrovascular complication Cardiovasc Res, February 1, 2007; 73(3): 504 - 511. [Abstract] [Full Text] [PDF]
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N. X. Chen, D. Duan, K. D. O'Neill, and S. M. Moe High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3435 - 3442. [Abstract] [Full Text] [PDF]
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C. J. O'Donnell, M. K. Shea, P. A. Price, D. R. Gagnon, P. W. F. Wilson, M. G. Larson, D. P. Kiel, U. Hoffmann, M. Ferencik, M. E. Clouse, et al. Matrix Gla Protein Is Associated With Risk Factors for Atherosclerosis but not With Coronary Artery Calcification Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2769 - 2774. [Abstract] [Full Text] [PDF]
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R. C. Johnson, J. A. Leopold, and J. Loscalzo Vascular Calcification: Pathobiological Mechanisms and Clinical Implications Circ. Res., November 10, 2006; 99(10): 1044 - 1059. [Abstract] [Full Text] [PDF]
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A. Galassi, D. M. Spiegel, A. Bellasi, G. A. Block, and P. Raggi Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders Nephrol. Dial. Transplant., November 1, 2006; 21(11): 3215 - 3222. [Abstract] [Full Text] [PDF]
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 J. R. Wu-Wong, W. Noonan, J. Ma, D. Dixon, M. Nakane, A. L. Bolin, K. A. Koch, S. Postl, S. J. Morgan, and G. A. Reinhart Role of Phosphorus and Vitamin D Analogs in the Pathogenesis of Vascular Calcification J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 90 - 98. [Abstract] [Full Text] [PDF]
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S. M. Moe and G. M. Chertow The Case against Calcium-Based Phosphate Binders Clin. J. Am. Soc. Nephrol., July 1, 2006; 1(4): 697 - 703. [Abstract] [Full Text] [PDF]
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X. Qin, M. A. Corriere, L. M. Matrisian, and R. J. Guzman Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1510 - 1516. [Abstract] [Full Text] [PDF]
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 A. H. E. M. Maas, Y. T. van der Schouw, D. Beijerinck, J. J. M. Deurenberg, W. P. T. M. Mali, and Y. van der Graaf Arterial Calcifications Seen on Mammograms: Cardiovascular Risk Factors, Pregnancy, and Lactation Radiology, July 1, 2006; 240(1): 33 - 38. [Abstract] [Full Text] [PDF]
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C. M. Shanahan Vascular calcification--a matter of damage limitation? Nephrol. Dial. Transplant., May 1, 2006; 21(5): 1166 - 1169. [Full Text] [PDF]
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Y. V. Bobryshev, R. S. A. Lord, and D. Tran Chlamydia pneumoniae in foci of "early" calcification of the tunica media in arteriosclerotic arteries: an incidental presence? Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1510 - H1519. [Abstract] [Full Text] [PDF]
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 J. S. Lee, D. M. Basalyga, A. Simionescu, J. C. Isenburg, D. T. Simionescu, and N. R. Vyavahare Elastin Calcification in the Rat Subdermal Model Is Accompanied by Up-Regulation of Degradative and Osteogenic Cellular Responses Am. J. Pathol., February 1, 2006; 168(2): 490 - 498. [Abstract] [Full Text] [PDF]
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 D. Hendig, V. Schulz, M. Arndt, C. Szliska, K. Kleesiek, and C. Gotting Role of Serum Fetuin-A, a Major Inhibitor of Systemic Calcification, in Pseudoxanthoma Elasticum Clin. Chem., February 1, 2006; 52(2): 227 - 234. [Abstract] [Full Text] [PDF]
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 C. J. Sullivan, T. H. Teal, I. P. Luttrell, K. B. Tran, M. A. Peters, and H. Wessells Microarray analysis reveals novel gene expression changes associated with erectile dysfunction in diabetic rats Physiol Genomics, October 17, 2005; 23(2): 192 - 205. [Abstract] [Full Text] [PDF]
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J. L. Reynolds, J. N. Skepper, R. McNair, T. Kasama, K. Gupta, P. L. Weissberg, W. Jahnen-Dechent, and C. M. Shanahan Multifunctional Roles for Serum Protein Fetuin-A in Inhibition of Human Vascular Smooth Muscle Cell Calcification J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2920 - 2930. [Abstract] [Full Text] [PDF]
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M. Y. Alexander, F. L. Wilkinson, J. P. Kirton, C. F. Rock, G. D.M. Collett, M. Jeziorska, J. V. Smyth, A. M. Heagerty, and A. E. Canfield Identification and Characterization of Vascular Calcification-Associated Factor, a Novel Gene Upregulated During Vascular Calcification In Vitro and In Vivo Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1851 - 1857. [Abstract] [Full Text] [PDF]
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 J. Adams and J. Pepping Vitamin K in the treatment and prevention of osteoporosis and arterial calcification Am. J. Health Syst. Pharm., August 1, 2005; 62(15): 1574 - 1581. [Abstract] [Full Text] [PDF]
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K. A. Lomashvili, W. Khawandi, and W. C. O'Neill Reduced Plasma Pyrophosphate Levels in Hemodialysis Patients J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2495 - 2500. [Abstract] [Full Text] [PDF]
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K. A. Hruska, S. Mathew, and G. Saab Bone Morphogenetic Proteins in Vascular Calcification Circ. Res., July 22, 2005; 97(2): 105 - 114. [Abstract] [Full Text] [PDF]
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G.D.M. Collett and A.E. Canfield Angiogenesis and Pericytes in the Initiation of Ectopic Calcification Circ. Res., May 13, 2005; 96(9): 930 - 938. [Abstract] [Full Text] [PDF]
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D. M. Basalyga, D. T. Simionescu, W. Xiong, B. T. Baxter, B. C. Starcher, and N. R. Vyavahare Elastin Degradation and Calcification in an Abdominal Aorta Injury Model: Role of Matrix Metalloproteinases Circulation, November 30, 2004; 110(22): 3480 - 3487. [Abstract] [Full Text] [PDF]
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J. L. Reynolds, A. J. Joannides, J. N. Skepper, R. McNair, L. J. Schurgers, D. Proudfoot, W. Jahnen-Dechent, P. L. Weissberg, and C. M. Shanahan Human Vascular Smooth Muscle Cells Undergo Vesicle-Mediated Calcification in Response to Changes in Extracellular Calcium and Phosphate Concentrations: A Potential Mechanism for Accelerated Vascular Calcification in ESRD J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2857 - 2867. [Abstract] [Full Text] [PDF]
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 N. Wajih, T. Borras, W. Xue, S. M. Hutson, and R. Wallin Processing and Transport of Matrix {gamma}-Carboxyglutamic Acid Protein and Bone Morphogenetic Protein-2 in Cultured Human Vascular Smooth Muscle Cells: EVIDENCE FOR AN UPTAKE MECHANISM FOR SERUM FETUIN J. Biol. Chem., October 8, 2004; 279(41): 43052 - 43060. [Abstract] [Full Text] [PDF]
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S. M. Moe and N. X. Chen Pathophysiology of Vascular Calcification in Chronic Kidney Disease Circ. Res., September 17, 2004; 95(6): 560 - 567. [Abstract] [Full Text] [PDF]
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 T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification Endocr. Rev., August 1, 2004; 25(4): 629 - 672. [Abstract] [Full Text] [PDF]
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 M. Schoppet, N. Al-Fakhri, F. E. Franke, N. Katz, P. J. Barth, B. Maisch, K. T. Preissner, and L. C. Hofbauer Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-{kappa}B Ligand in Monckeberg's Sclerosis and Atherosclerosis J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4104 - 4112. [Abstract] [Full Text] [PDF]
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G. M. London, C. Marty, S. J. Marchais, A. P. Guerin, F. Metivier, and M.-C. de Vernejoul Arterial Calcifications and Bone Histomorphometry in End-Stage Renal Disease J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1943 - 1951. [Abstract] [Full Text] [PDF]
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K. A. Lomashvili, S. Cobbs, R. A. Hennigar, K. I. Hardcastle, and W. C. O'Neill Phosphate-Induced Vascular Calcification: Role of Pyrophosphate and Osteopontin J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1392 - 1401. [Abstract] [Full Text] [PDF]
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 R. Vattikuti and D. A. Towler Osteogenic regulation of vascular calcification: an early perspective Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E686 - E696. [Abstract] [Full Text] [PDF]
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Z. Aherrahrou, S. B. Axtner, P. M. Kaczmarek, A. Jurat, S. Korff, L. C. Doehring, D. Weichenhan, H. A. Katus, and B. T. Ivandic A Locus on Chromosome 7 Determines Dramatic Up-Regulation of Osteopontin in Dystrophic Cardiac Calcification in Mice Am. J. Pathol., April 1, 2004; 164(4): 1379 - 1387. [Abstract] [Full Text] [PDF]
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G. M. London, A. P. Guerin, S. J. Marchais, F. Metivier, B. Pannier, and H. Adda Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality Nephrol. Dial. Transplant., September 1, 2003; 18(9): 1731 - 1740. [Abstract] [Full Text] [PDF]
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K. L. Tyson, J. L. Reynolds, R. McNair, Q. Zhang, P. L. Weissberg, and C. M. Shanahan Osteo/Chondrocytic Transcription Factors and Their Target Genes Exhibit Distinct Patterns of Expression in Human Arterial Calcification Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 489 - 494. [Abstract] [Full Text] [PDF]
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T. Shigematsu, T. Kono, K. Satoh, K. Yokoyama, T. Yoshida, T. Hosoya, and K. Shirai Phosphate overload accelerates vascular calcium deposition in end-stage renal disease patients Nephrol. Dial. Transplant., March 1, 2003; 18(90003): iii86 - 89. [Abstract] [Full Text] [PDF]
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D. Proudfoot, J.D. Davies, J.N. Skepper, P.L. Weissberg, and C.M. Shanahan Acetylated Low-Density Lipoprotein Stimulates Human Vascular Smooth Muscle Cell Calcification by Promoting Osteoblastic Differentiation and Inhibiting Phagocytosis Circulation, December 10, 2002; 106(24): 3044 - 3050. [Abstract] [Full Text] [PDF]
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 M. Y. Speer, M. D. McKee, R. E. Guldberg, L. Liaw, H.-Y. Yang, E. Tung, G. Karsenty, and C. M. Giachelli Inactivation of the Osteopontin Gene Enhances Vascular Calcification of Matrix Gla Protein-deficient Mice: Evidence for Osteopontin as an Inducible Inhibitor of Vascular Calcification In Vivo J. Exp. Med., October 21, 2002; 196(8): 1047 - 1055. [Abstract] [Full Text] [PDF]
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A. Shioi, M. Katagi, Y. Okuno, K. Mori, S. Jono, H. Koyama, and Y. Nishizawa Induction of Bone-Type Alkaline Phosphatase in Human Vascular Smooth Muscle Cells: Roles of Tumor Necrosis Factor-{alpha} and Oncostatin M Derived From Macrophages Circ. Res., July 12, 2002; 91(1): 9 - 16. [Abstract] [Full Text] [PDF]
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 C. Top, Z. Cankir, E. Silit, S. Yildirim, and M. Danaci Monckeberg's Sclerosis: An Unusual Presentation: A Case Report Angiology, July 1, 2002; 53(4): 483 - 486. [Abstract] [PDF]
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D. Goldsmith, R. MacGinley, A. Smith, and A. Covic How important and how treatable is vascular stiffness as a cardiovascular risk factor in renal failure? Nephrol. Dial. Transplant., June 1, 2002; 17(6): 965 - 969. [Full Text] [PDF]
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U. Querfeld Is atherosclerosis accelerated in young patients with end-stage renal disease? The contribution of paediatric nephrology Nephrol. Dial. Transplant., May 1, 2002; 17(5): 719 - 722. [Full Text] [PDF]
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 Q. Zhang, J. N. Skepper, F. Yang, J. D. Davies, L. Hegyi, R. G. Roberts, P. L. Weissberg, J. A. Ellis, and C. M. Shanahan Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues J. Cell Sci., March 14, 2002; 114(24): 4485 - 4498. [Abstract] [Full Text] [PDF]
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M. A Engelse, J. M Neele, A. L.J.J Bronckers, H. Pannekoek, and C. J.M de Vries Vascular calcification: expression patterns of the osteoblast-specific gene core binding factor {alpha}-1 and the protective factor matrix gla protein in human atherogenesis Cardiovasc Res, November 1, 2001; 52(2): 281 - 289. [Abstract] [Full Text] [PDF]
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L. L. Demer Cholesterol in Vascular and Valvular Calcification Circulation, October 16, 2001; 104(16): 1881 - 1883. [Full Text] [PDF]
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P. A. Price, S. A. Faus, and M. K. Williamson Bisphosphonates Alendronate and Ibandronate Inhibit Artery Calcification at Doses Comparable to Those That Inhibit Bone Resorption Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 817 - 824. [Abstract] [Full Text] [PDF]
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 A Farzaneh-Far, D Proudfoot, C Shanahan, and P L Weissberg Vascular and valvar calcification: recent advances Heart, January 1, 2001; 85(1): 13 - 17. [Full Text]
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A. Farzaneh-Far, J. D. Davies, L. A. Braam, H. M. Spronk, D. Proudfoot, S.-W. Chan, K. M. O'Shaughnessy, P. L. Weissberg, C. Vermeer, and C. M. Shanahan A Polymorphism of the Human Matrix gamma -Carboxyglutamic Acid Protein Promoter Alters Binding of an Activating Protein-1 Complex and Is Associated with Altered Transcription and Serum Levels J. Biol. Chem., August 24, 2001; 276(35): 32466 - 32473. [Abstract] [Full Text] [PDF]
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