Regulatory mechanisms in vascular calcification

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.

[1]  Yin Tintut,et al.  Systems biology of vascular calcification. , 2009, Trends in cardiovascular medicine.

[2]  D. Towler Vascular calcification in ESRD: Another cloud appears in the perfect storm--but highlights a silver lining? , 2004, Kidney international.

[3]  L. Demer,et al.  Matrix GLA Protein Modulates Differentiation Induced by Bone Morphogenetic Protein-2 in C3H10T1/2 Cells* , 2001, The Journal of Biological Chemistry.

[4]  Y. Ouchi,et al.  Adiponectin antagonizes stimulatory effect of tumor necrosis factor-alpha on vascular smooth muscle cell calcification: regulation of growth arrest-specific gene 6-mediated survival pathway by adenosine 5'-monophosphate-activated protein kinase. , 2008, Endocrinology.

[5]  F. Parhami,et al.  Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. , 2001, Free radical biology & medicine.

[6]  J. Skepper,et al.  Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. , 2005, Journal of the American Society of Nephrology : JASN.

[7]  K. Hruska,et al.  Function and effect of bone morphogenetic protein‐7 in kidney bone and the bone‐vascular links in chronic kidney disease , 2006, European journal of clinical investigation.

[8]  A. Schilling,et al.  Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function. , 2008, Bone.

[9]  J. Skepper,et al.  Apoptosis Regulates Human Vascular Calcification In Vitro: Evidence for Initiation of Vascular Calcification by Apoptotic Bodies , 2000, Circulation research.

[10]  S. Niida,et al.  ApoE Gene Deficiency Enhances the Reduction of Bone Formation Induced by a High‐Fat Diet Through the Stimulation of p53‐Mediated Apoptosis in Osteoblastic Cells , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[11]  Michael L J Apuzzo Gravitas, Severitas, Veritas, Virtus. , 2006, Neurosurgery.

[12]  Frederick J Schoen,et al.  SnapShot: calcification of bioprosthetic heart valves. , 2009, Biomaterials.

[13]  D. Jacobs,et al.  Abdominal obesity and coronary artery calcification in young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. , 2007, The American journal of clinical nutrition.

[14]  Qingbo Xu,et al.  Soluble Receptor Activator of Nuclear Factor-&kgr;B Ligand and Risk for Cardiovascular Disease , 2007, Circulation.

[15]  Renu Virmani,et al.  Histopathology of Carotid Atherosclerotic Disease , 2006, Neurosurgery.

[16]  C. Wanner,et al.  Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study , 2003, The Lancet.

[17]  R. Effros,et al.  Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss. , 2009, Clinical immunology.

[18]  J. Skepper,et al.  Acetylated Low-Density Lipoprotein Stimulates Human Vascular Smooth Muscle Cell Calcification by Promoting Osteoblastic Differentiation and Inhibiting Phagocytosis , 2002, Circulation.

[19]  C. Shanahan Mechanisms of vascular calcification in renal disease. , 2005, Clinical nephrology.

[20]  Su‐Li Cheng,et al.  Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. , 2005, The Journal of clinical investigation.

[21]  P. Weissberg,et al.  Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification , 2006, Journal of internal medicine.

[22]  Z. Al-Aly,et al.  Aortic Msx2-Wnt Calcification Cascade Is Regulated by TNF-&agr;–Dependent Signals in Diabetic Ldlr−/− Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[23]  F. Parhami,et al.  Atherogenic High‐Fat Diet Reduces Bone Mineralization in Mice , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[24]  S. Kihara,et al.  Periadventitial Adipose Tissue Plays a Critical Role in Vascular Remodeling , 2009, Circulation research.

[25]  E. Mohler Mechanisms of aortic valve calcification. , 2004, The American journal of cardiology.

[26]  C. Shanahan,et al.  Stromal cells of fibrodysplasia ossificans progressiva lesions express smooth muscle lineage markers and the osteogenic transcription factor Runx2/Cbfa‐1: clues to a vascular origin of heterotopic ossification? , 2003, The Journal of pathology.

[27]  S. Badylak,et al.  A perivascular origin for mesenchymal stem cells in multiple human organs. , 2008, Cell stem cell.

[28]  S. Morony,et al.  Hyperlipidemia Promotes Osteoclastic Potential of Bone Marrow Cells Ex Vivo , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[29]  J. Kappes,et al.  Oxidative Stress Induces Vascular Calcification through Modulation of the Osteogenic Transcription Factor Runx2 by AKT Signaling* , 2008, Journal of Biological Chemistry.

[30]  R. Terkeltaub,et al.  Chondrogenesis Mediated by PPi Depletion Promotes Spontaneous Aortic Calcification in NPP1−/− Mice , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[31]  R. Boot-Handford,et al.  Receptor Tyrosine Kinase Axl Modulates the Osteogenic Differentiation of Pericytes , 2003, Circulation research.

[32]  J. V. van Engelshoven,et al.  Vascular calcifications as a marker of increased cardiovascular risk: A meta-analysis , 2009, Vascular health and risk management.

[33]  G. Cossu,et al.  Mesoangioblasts--vascular progenitors for extravascular mesodermal tissues. , 2003, Current opinion in genetics & development.

[34]  Xianwu Li,et al.  Role of the Sodium-Dependent Phosphate Cotransporter, Pit-1, in Vascular Smooth Muscle Cell Calcification , 2006, Circulation research.

[35]  H. Kruth,et al.  Detection of cholesterol associated with calcium mineral using confocal fluorescence microscopy. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[36]  J. Kerr,et al.  Atlas of Functional Histology , 1999 .

[37]  C. Giachelli Vascular calcification mechanisms. , 2004, Journal of the American Society of Nephrology : JASN.

[38]  R. Behringer,et al.  Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein , 1997, Nature.

[39]  L. Schurgers,et al.  Post‐translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification , 2007, Journal of thrombosis and haemostasis : JTH.

[40]  H. Ryoo,et al.  Tumor necrosis factor-alpha increases alkaline phosphatase expression in vascular smooth muscle cells via MSX2 induction. , 2010, Biochemical and biophysical research communications.

[41]  D. Kiel,et al.  Calcifications in the Abdominal Aorta Predict Fractures in Men: MINOS Study , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[42]  M. Daemen,et al.  Atherosclerotic plaque rupture: local or systemic process? , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[43]  B. Sacchetti,et al.  Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells , 2007, Nature Cell Biology.

[44]  P. Libby,et al.  Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease , 2009, Circulation.

[45]  A. Canfield,et al.  Vascular Pericytes Express Osteogenic Potential In Vitro and In Vivo , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[46]  O. Florey,et al.  Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways: A Vicious Cycle of Inflammation and Arterial Calcification? , 2005, Circulation research.

[47]  Xianwu Li,et al.  BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells. , 2008, Atherosclerosis.

[48]  R. Terkeltaub,et al.  Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. , 2004, The American journal of pathology.

[49]  J. Tobis,et al.  Mechanical stress analysis of a rigid inclusion in distensible material: a model of atherosclerotic calcification and plaque vulnerability. , 2009, American journal of physiology. Heart and circulatory physiology.

[50]  Sungyoul Hong,et al.  Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. , 2009, Blood.

[51]  D. Kiel,et al.  Matrix Gla Protein Is Associated With Risk Factors for Atherosclerosis but not With Coronary Artery Calcification , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[52]  J. Skepper,et al.  Mineral Surface in Calcified Plaque Is Like That of Bone: Further Evidence for Regulated Mineralization , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[53]  H. Cheung,et al.  Basic calcium phosphate crystals activate c-fos expression through a Ras/ERK dependent signaling mechanism. , 2007, Biochemical and biophysical research communications.

[54]  N. Chen,et al.  Fetuin-A uptake in bovine vascular smooth muscle cells is calcium dependent and mediated by annexins. , 2007, American journal of physiology. Renal physiology.

[55]  K. K. Quan,et al.  Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. , 2009, Kidney international.

[56]  R. Terkeltaub,et al.  Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy , 2008, Circulation. Cardiovascular genetics.

[57]  Y. Ouchi,et al.  Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells. , 2007, European journal of pharmacology.

[58]  J. Butany,et al.  Peripheral vascular disease: who gets it and why? A histomorphological analysis of 261 arterial segments from 58 cases , 2008, Pathology.

[59]  L. Demer Effect of calcification on in vivo mechanical response of rabbit arteries to balloon dilation. , 1991, Circulation.

[60]  T. Littlewood,et al.  Chronic Apoptosis of Vascular Smooth Muscle Cells Accelerates Atherosclerosis and Promotes Calcification and Medial Degeneration , 2008, Circulation research.

[61]  N. Rajamannan Calcific aortic stenosis: lessons learned from experimental and clinical studies. , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[62]  R. Pignolo,et al.  The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signaling. , 2009, Cytokine & growth factor reviews.

[63]  M. Razzaque,et al.  Does Fgf23-klotho activity influence vascular and soft tissue calcification through regulating mineral ion metabolism? , 2008, Kidney international.

[64]  F. Parhami,et al.  Leptin Enhances the Calcification of Vascular Cells: Artery Wall as a Target of Leptin , 2001, Circulation research.

[65]  K. Watson,et al.  Bone morphogenetic protein expression in human atherosclerotic lesions. , 1993, The Journal of clinical investigation.

[66]  R. Terkeltaub,et al.  Transglutaminase 2 Is Central to Induction of the Arterial Calcification Program by Smooth Muscle Cells , 2008, Circulation research.

[67]  M. Butcher,et al.  Oxidized low‐density lipoprotein acts synergistically with β‐glycerophosphate to induce osteoblast differentiation in primary cultures of vascular smooth muscle cells , 2008, Journal of cellular biochemistry.

[68]  Su‐Li Cheng,et al.  Inflammation and the osteogenic regulation of vascular calcification: a review and perspective. , 2010, Hypertension.

[69]  G. London,et al.  Impairment of arterial function in chronic renal disease: prognostic impact and therapeutic approach. , 2002, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[70]  A. Nicolaides,et al.  Investigation of chronic venous insufficiency: A consensus statement (France, March 5-9, 1997). , 2000, Circulation.

[71]  Craig A Simmons,et al.  Calcification by Valve Interstitial Cells Is Regulated by the Stiffness of the Extracellular Matrix , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[72]  G. Francis,et al.  Vascular Calcifications in Homozygote Familial Hypercholesterolemia , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[73]  R. Virchow,et al.  Cellular Pathology, as Based upon Physiological and Pathological Histology , 1860, Nutrition reviews.

[74]  Alexandra E. Ewence,et al.  Calcium Phosphate Crystals Induce Cell Death in Human Vascular Smooth Muscle Cells: A Potential Mechanism in Atherosclerotic Plaque Destabilization , 2008, Circulation research.

[75]  G. Bishop,et al.  Regulation of interleukin-6 expression in osteoblasts by oxidized phospholipids , 2010, Journal of Lipid Research.

[76]  V F Froelicher,et al.  American College of Cardiology/American Heart Association Expert Consensus Document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. , 2000, Journal of the American College of Cardiology.

[77]  B. Coll,et al.  RANKL Increases Vascular Smooth Muscle Cell Calcification Through a RANK-BMP4–Dependent Pathway , 2009, Circulation research.

[78]  T. Akizawa,et al.  Elastin Degradation Accelerates Phosphate-Induced Mineralization of Vascular Smooth Muscle Cells , 2009, Calcified Tissue International.

[79]  C. McCollum,et al.  Observations on bone formation and remodelling in advanced atherosclerotic lesions of human carotid arteries , 1998, Virchows Archiv.

[80]  C. Holt,et al.  Role of calcium phosphate nanoclusters in the control of calcification , 2009, The FEBS journal.

[81]  S. Morony,et al.  osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. , 1998, Genes & development.

[82]  E. Andreeva,et al.  Continuous subendothelial network formed by pericyte-like cells in human vascular bed. , 1998, Tissue & cell.

[83]  J. Thyberg,et al.  Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[84]  W. Jacob,et al.  Apoptosis and related proteins in different stages of human atherosclerotic plaques. , 1998, Circulation.

[85]  E. Bassi,et al.  Oxidant Generation Predominates Around Calcifying Foci and Enhances Progression of Aortic Valve Calcification , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[86]  Y. Tintut,et al.  Vitamin D and osteogenic differentiation in the artery wall. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[87]  S. Morony,et al.  Atherogenic Phospholipids Attenuate Osteogenic Signaling by BMP-2 and Parathyroid Hormone in Osteoblasts* , 2007, Journal of Biological Chemistry.

[88]  Pedagógia,et al.  Cross Sectional Study , 2019 .

[89]  G. Yvert,et al.  Genome‐wide expression analyses establish dendritic cells as a new osteoclast precursor able to generate bone‐resorbing cells more efficiently than monocytes , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[90]  L. Liaw,et al.  Osteopontin: A Multifunctional Molecule Regulating Chronic Inflammation and Vascular Disease , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[91]  Y. Tintut,et al.  Insulin-Like Growth Factor-I Regulates Proliferation and Osteoblastic Differentiation of Calcifying Vascular Cells via Extracellular Signal-Regulated Protein Kinase And Phosphatidylinositol 3-Kinase Pathways , 2005, Circulation research.

[92]  D. Dichek,et al.  Smooth Muscle Cells Give Rise to Osteochondrogenic Precursors and Chondrocytes in Calcifying Arteries , 2009, Circulation research.

[93]  Brian J. Bennett,et al.  Calcification of Advanced Atherosclerotic Lesions in the Innominate Arteries of ApoE-Deficient Mice: Potential Role of Chondrocyte-Like Cells , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[94]  G. Werstuck,et al.  Effect of Leptin on Vascular Calcification in Apolipoprotein E–Deficient Mice , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[95]  Y. Ouchi,et al.  Statins Protect Human Aortic Smooth Muscle Cells From Inorganic Phosphate-Induced Calcification by Restoring Gas6-Axl Survival Pathway , 2006, Circulation research.

[96]  Daniel A Fletcher,et al.  Tissue Geometry Determines Sites of Mammary Branching Morphogenesis in Organotypic Cultures , 2006, Science.

[97]  O. Tawfik,et al.  Isolation of calcifiable vesicles from aortas of rabbits fed with high cholesterol diets. , 2000, Atherosclerosis.

[98]  P. D’Haese,et al.  Chondrocyte Rather Than Osteoblast Conversion of Vascular Cells Underlies Medial Calcification in Uremic Rats , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[99]  P. Price,et al.  Osteoprotegerin Inhibits Artery Calcification Induced by Warfarin and by Vitamin D , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[100]  C. Otto,et al.  Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[101]  Y. Ouchi,et al.  Androgen Receptor-dependent Transactivation of Growth Arrest-specific Gene 6 Mediates Inhibitory Effects of Testosterone on Vascular Calcification* , 2010, The Journal of Biological Chemistry.

[102]  M. Fishbein,et al.  Cartilaginous metaplasia in calcified diabetic peripheral vascular disease: morphologic evidence of enchondral ossification. , 2003, Human pathology.

[103]  Y. Tintut,et al.  Vascular calcification: mechanisms and clinical ramifications. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[104]  F. Parhami,et al.  cAMP Stimulates Osteoblast-like Differentiation of Calcifying Vascular Cells , 1998, The Journal of Biological Chemistry.

[105]  H. Xie,et al.  Development of Arterial Calcification in Adiponectin‐Deficient Mice: Adiponectin Regulates Arterial Calcification , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[106]  M. McKee,et al.  Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. , 2005, Genes & development.

[107]  M. A. Sheddi A clinicopathological study , 2012 .

[108]  K. Hruska,et al.  PHOSPHORUS METABOLISM AND MANAGEMENT IN CHRONIC KIDNEY DISEASE: Renal Osteodystrophy, Phosphate Homeostasis, and Vascular Calcification , 2007, Seminars in dialysis.

[109]  K. Watson,et al.  Multilineage Potential of Cells From the Artery Wall , 2003, Circulation.

[110]  Yin Tintut,et al.  8-Isoprostaglandin E2 Enhances Receptor-activated NFκB Ligand (RANKL)-dependent Osteoclastic Potential of Marrow Hematopoietic Precursors via the cAMP Pathway* , 2002, The Journal of Biological Chemistry.

[111]  R. Brooks,et al.  Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. , 2008, Journal of the American College of Cardiology.

[112]  T. Friščić,et al.  The mineral phase of calcified cartilage: its molecular structure and interface with the organic matrix. , 2009, Biophysical journal.

[113]  C. Bunting THE FORMATION OF TRUE BONE WITH CELLULAR (RED) MARROW IN A SCLEROTIC AORTA , 1906, The Journal of experimental medicine.

[114]  G. London,et al.  Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia , 2005, Current opinion in nephrology and hypertension.

[115]  P. Weissberg,et al.  Osteo/Chondrocytic Transcription Factors and Their Target Genes Exhibit Distinct Patterns of Expression in Human Arterial Calcification , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[116]  R. Fairman,et al.  Bone Formation in Carotid Plaques: A Clinicopathological Study , 2002, Stroke.

[117]  A. Canfield,et al.  Chondrogenic and Adipogenic Potential of Microvascular Pericytes , 2004, Circulation.

[118]  M. Frid,et al.  Mature Vascular Endothelium Can Give Rise to Smooth Muscle Cells via Endothelial-Mesenchymal Transdifferentiation: In Vitro Analysis , 2002, Circulation research.

[119]  W. Arap,et al.  A Population of Multipotent CD34-Positive Adipose Stromal Cells Share Pericyte and Mesenchymal Surface Markers, Reside in a Periendothelial Location, and Stabilize Endothelial Networks , 2008, Circulation research.

[120]  D. Milewicz,et al.  An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. , 2009, The Journal of clinical investigation.

[121]  N. Chen,et al.  High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[122]  L. Chaudhary,et al.  The mechanism of phosphorus as a cardiovascular risk factor in CKD. , 2008, Journal of the American Society of Nephrology : JASN.

[123]  A. Watson,et al.  Heat Shock Protein 70 Enhances Vascular Bone Morphogenetic Protein-4 Signaling by Binding Matrix Gla Protein , 2009, Circulation research.

[124]  F. Parhami,et al.  Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[125]  S. Stock,et al.  Atorvastatin Inhibits Hypercholesterolemia-Induced Calcification in the Aortic Valves via the Lrp5 Receptor Pathway , 2005, Circulation.

[126]  W. Richtering,et al.  Hierarchical Role of Fetuin-A and Acidic Serum Proteins in the Formation and Stabilization of Calcium Phosphate Particles* , 2008, Journal of Biological Chemistry.

[127]  Su‐Li Cheng,et al.  Teriparatide (Human Parathyroid Hormone (1–34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice* , 2003, Journal of Biological Chemistry.

[128]  Yin Tintut,et al.  Hyperlipidemia Impairs Osteoanabolic Effects of PTH , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[129]  A. Gilmore,et al.  Axl/Phosphatidylinositol 3-Kinase Signaling Inhibits Mineral Deposition by Vascular Smooth Muscle Cells , 2007, Circulation research.

[130]  Y. Tintut,et al.  Mechanisms and Clinical Ramifications , 2004 .

[131]  Daniel S Berman,et al.  Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. , 2007, Journal of the American College of Cardiology.

[132]  Michael J. Pencina,et al.  Vitamin D Deficiency and Risk of Cardiovascular Disease , 2008, Circulation.

[133]  H. C. Stary Natural history of calcium deposits in atherosclerosis progression and regression , 2000, Zeitschrift für Kardiologie.

[134]  L. Schurgers,et al.  Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis , 2008, Circulation.

[135]  N. Chen,et al.  Pathophysiology of Vascular Calcification in Chronic Kidney Disease , 2004, Circulation research.

[136]  B. Draznin,et al.  Insulin attenuates vascular smooth muscle calcification but increases vascular smooth muscle cell phosphate transport. , 2007, Atherosclerosis.

[137]  V. Persy,et al.  Vascular calcification and bone disease: the calcification paradox. , 2009, Trends in molecular medicine.

[138]  F. Schmidt Meta-Analysis , 2008 .

[139]  K. Boström,et al.  Matrix GLA Protein, a Regulatory Protein for Bone Morphogenetic Protein-2* , 2002, The Journal of Biological Chemistry.

[140]  J. Blacher,et al.  Arterial Calcifications, Arterial Stiffness, and Cardiovascular Risk in End-Stage Renal Disease , 2001, Hypertension.