Calcification is a prominent feature of atherosclerosis, frequently associated with myocardial infarction and other adverse cardiovascular outcomes. Currently, calcification is widely viewed as an end-stage, degenerative process which is inevitable in advanced atherosclerosis. Pathologists, however, have long noted that calcification may occur early in atherosclerosis and, at times, may appear histologically identical to organized bone, including areas resembling bone marrow. These observations suggest that rather than being a passive process, atherosclerotic calcification may instead be an active, regulated process similar to that of osteogenesis. Using an in-vitro model of arterial calcification a subpopulation of artery wall cells, capable of producing hydroxyapatite mineral in vitro was discovered. This article discusses some of the cellular and molecular mechanisms of arterial calcification identified utilizing this in-vitro model of vascular calcification.
VirchowR.Cellular pathology: as based upon physiological and pathological histology (translated by Frank Chance, 1971), an unabridged and unaltered re-publication of the English translation originally published in Dover; 1863. pp. 404–408.
2.
MorgagniD.De sedibus et causis morborum per anatomen indagatis. Venice, Italy: Ex Typographia Remondiana; 1761. Cited by: Bing R. Coronary circulation and cardiac metabolism. In: FishmanARichardsD (editors): Circulation of the blood: men and ideas.Oxford, UK: Oxford University Press; 1964. pp. 199–264.
3.
HonyeJMahonDJainAWhiteCRameeSWallisJ. Morphological effects of coronary balloon angioplasty in vivo assessed by intravascular ultrasound imaging. Circulation1996; 93: 1951–1953.
4.
AgatsonAJanowitzWHildnerFZusmerNViamonteMDetranoR.Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol1990; 15: 827–832.
5.
LongER.Development of our knowledge of arteriosclerosis. In: BlumenthalHT (editor): Cowdry's arteriosclerosis, a survey of the problem 1967.Springfield: Charles C. Thomas Publishers, pp. 6–7.
6.
HaustMDMoreRH.Spontaneous lesions of the aorta in the rabbit. In: RobertsJCStrausR (editors): Comparative atherosclerosis: the morphology of spontaneous and induced atherosclerotic lesions in the animals and it's relation to human disease.New York: Harper and Row; 1965. pp. 255–275.
7.
AlexanderRW.Diagnostic electron microscopy of bone. In: TrumpBFJonesRT (editors): Diagnostic electron microscopy.New York: John Wiley and Sons; 1983. p. 429.
8.
SchmidKMcSharryWOPameijerCHBinetteJP.Chemical and physiochemical studies on the mineral deposits of the human atherosclerotic aorta. Atherosclerosis1980; 37: 199–210.
9.
AndersonHC.Calcific diseases: a concept. Arch Pathol Lab Med1983; 107: 341–348.
10.
AndersonHC.Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol1969; 41: 59–72.
11.
TanimuraAMcGregorDHAndersonHC.Calcification in atherosclerosis I. Human studies. J Exp Pathol1986; 2: 261–273.
12.
KimKM.Calcification of matrix vesicles in human aortic valve and aortic media. Fed Proc1976; 35: 156–162.
13.
HirotaSMasamiIKohriKItoAMorriEAdachiS. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques. A possible association with calcification. Am J Pathol1993; 143: 1003–1008.
14.
GiachelliCMBaeNAlmeidaMDenhardtDTAlpersCESchwartzSM.Osteopontin is elevated during neointima formation in rat arteries and is a normal component of human atherosclerotic plaques. J Clin Invest1993; 92: 1686–1696.
15.
IkedaTShirasawaTEsakiYYoshikiSHirokawaK.Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta. J Clin Invest1993; 92: 2814–2820.
16.
RekhterMDZhangKNarayananASPhanSSchookMAGordonD.Type I collagen gene expression in human atherosclerosis. Am J Pathol1993; 143: 1634–1648.
17.
FitzpatrickLASeversonAEdwardsWDIngramRT.Diffuse calcification in human coronary arteries: association of osteopontin with atherosclerosis. J Clin Invest1994; 94: 1597–1604.
18.
FleetJCHockJM.Identification of osteocalcin mRNA in nonosteroid tissue of rats and humans by reverse transcription-polymerase chain reaction. J Bone Miner Res1994; 9: 1565–1573.
19.
O'BrienERGarvinMRStewartDRHinoharaTSimpsonJBSchwartzSM. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb1994; 14: 1648–1656.
20.
ShanahanCMCaryNRBMetcalfeJCWeissbergPL.High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest1994; 93: 2393–2402.
21.
BoströmKWatsonKEHornSWorthamCHermanIMDemerLL.Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest1993; 91: 1800–1809.
22.
In this study, the most potent osteogenic factor known (bone morphogenetic protein) was detected in calcified human atherosclerotic lesions. This finding supported the hypothesis that bone formation and development of atherosclerotic calcification were similar.
23.
WatsonKESchaubBMaloneLDemerLL.A subpopulation of vascular cells supports hematopoiesis and expresses stem cell factor [abstract]. Atherosclerosis1997; 134: 277.
24.
WatsonKEBoströmKRavindranathRLamTNortonBDemerLL.TGF-β1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest1994; 93: 2106–2113.
25.
In this study a novel subpopulation of artery wall cells was discovered. These cells possessed many features consistent with an osteoblastic lineage and answered the key question of which cells might be responsible for producing atherosclerotic calcification.
26.
ShapiroIMWuthierREIrvingJT.A study of the phospholipids of bovine dental tissues. I. Enamel matrix and dentin. Arch Oral Biol1966; 11: 501–512.
27.
EnlowDHConklinJL.A study of lipid distribution in compact bone [abstract]. Anat Rec1964; 148: 279.
28.
IrvingJTWuthierRE.Histochemistry and biochemistry of calcification with special reference to the role of lipids. Clin Orthop1968; 56: 237–260.
29.
ConklinJLEnlowDHBangS.Methods for the demonstration of lipid applied to compact bone. Stain Technol1965; 40: 183–191.
30.
ShapiroIM.The lipids of skeletal and dental tissues: their role in mineralization. In: ZipkinI (editor): Biological mineralization I.New York: Wiley; pp. 117–138.
31.
RossiMABraileDMTeixeiraMDSouzaDRPeresLC.Lipid extraction attenuates the calcific degeneration of bovine pericardium used in cardiac valve bioprostheses. J Exp Path1990; 71: 187–196.
32.
Jorge-HerreroEFernandezPGutierrezMCastillo-OlivaresJC.Study of the calcification of bovine pericardium: analysis of the implication of lipids and proteoglycans. Biomaterials1991; 12: 683–689.
33.
Jorge-HerreroEFernandezPde la TorreNEscuderoCGarcia-PaezJMBujanJ. Inhibition of the calcification of porcine valve tissue by selective lipid removal. Biomaterials1994; 15: 815–820.
34.
HirschDAzouryRSarigSKrithHS.Colocalization of cholesterol and hydroxyapatite in human atherosclerotic lesions. Calcif Tissue Int1993; 52: 94–98.
35.
SarigSWeissTAKatzIKahanaFAzouryROkonE. Detection of cholesterol associated with calcium mineral using confocal fluorescence microscopy. Lab Invest1994; 71: 782–787.
36.
RokitaECichockiTHeckDJarczykLStrzalkowskiA.Calcification of aortic wall in cholesterol-fed rabbits. Atherosclerosis1991; 87: 183–193.
37.
AliSYWisbyAGrayJC.Electron probe analysis of cryosections of epiphyseal cartilage. Metab Bone Dis1978; 1: 97–103.
38.
AliSY.Analysis of matrix vesicles and their role in the calcification of epiphyseal cartilage. Fed Proc1976; 35: 135–142.
39.
GuytonJRKlempKF.Development of the atherosclerotic core region. Chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta. Arterioscler Thromb1994; 14: 1305–1314.
40.
MarumGJ.Roentgenographic observations in age atrophy and osteoporosis of the spine. Radiology1946; 46: 220–226.
41.
ElkelesA.A comparative radiological study of calcified atheroma in males and females over 50 years of age. Lancet1957; Oct. 12:714–715.
42.
AndersonJBBarnettENordinBEC.The relationship between osteoporosis and aortic calcification. Brit J Radiol1964; 37: 910–912.
43.
DentCEEngelbrechtHEGodfreyRC.Osteoporosis of lumbar vertebrae and calcification of abdominal aorta in women living in Durban. BMJ1968; 4: 76–79.
44.
FujitaTOkamotoYSakagamiYOtaKOhataM.Bone changes and aortic calcification in aging inhabitants of mountain versus seacoast communities in the Kii peninsula. J Am Geriat Soc1984; 32: 124–128.
45.
BrownerWSPressmanARNevittMCCauleyJACummingsSR.Association between low bone density and stroke in elderly women; the study of osteoporotic fractures. Stroke1993; 24: 940–946.
46.
BanksLMLeesBMacsweeneyJEStevensonJC.Effect of degenerative spinal and aortic calcification on bone density measurements in post-menopausal women: links between osteoporosis and cardiovascular disease?Eur J Clin Invest1994; 24: 813–817.
47.
ParhamiFMorrowADBalucanJLeitingerNWatsonADTintutY. 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. Arterioscler Thromb Vasc Biol1997; 17: 680–687.
48.
To assess the potential role of lipoproteins in the processes of arterial calcification and osteoporosis, the authors examined the effects of minimally oxidized low-density lipoprotein and several other lipid oxidation products on in-vitro calcification of both vascular and bone cells. They found that the lipid oxidation products promoted calcification of the vascular cells while inhibiting calcification of the bone cells, offering a potential explanation for the coexistence of both arterial calcification and osteoporosis in certain individuals.
49.
WatsonKEParhamiFShinVDemerLL.Fibreonectin and collagen I matrixes promote calcification of vascular cells in vitro, whereas collagen IV matrix is inhibitory. Arterioscler Thromb Vasc Biol1998; 18: 1964–1971.
50.
This study investigated the role of extracellular matrix in development of vascular calcification. The finding that certain extracellular matrix molecules potentiate vascular calcification while others may inhibit it lends understanding to the developmental mechanisms of vascular calcification and also helps explain the colocalization of atherosclerosis and calcification in vivo..
51.
QiaoJXiePFishbeinMCKreuzerJDrakeTADemerLL. Pathology of atheromatous lesions in inbred and genetically engineered mice: genetic determination of arterial calcification. Arterioscl Thromb1994; 14: 1480–1497.
