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Ultrastructural, Elemental and Mineralogical Analysis of Vascular Calcification in Atherosclerosis

Published online by Cambridge University Press:  06 September 2017

Ida Perrotta  and
Edoardo Perri
Ida Perrotta*
Affiliation:
Department of Biology, Ecology and Earth Sciences (Di.B.E.S.T.), University of Calabria, Arcavacata di Rende (Cosenza) 87036, Italy
Edoardo Perri
Affiliation:
Department of Biology, Ecology and Earth Sciences (Di.B.E.S.T.), University of Calabria, Arcavacata di Rende (Cosenza) 87036, Italy
*
*Corresponding author. idaperrotta@yahoo.it
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Abstract

Over the past few decades, remarkable progress has been achieved in terms of understanding the molecular and cellular mechanisms of atherosclerotic vascular calcification and the important role of matrix vesicles in initiating and propagating pathologic tissue mineralization has been widely recognized. Despite these recent advances, however, no definitive data are currently available regarding the texture and composition of the minerals that grow in the vessel wall during the course of the disease. Using different electron microscopy imaging and analysis, we demonstrate that vascular cells can produce and secrete more than one type of matrix vesicles which act as sites for initial mineral deposition independently of their structural features. Our results reveal that apatite formation in the atherosclerotic lesions of the human aorta occur through the deposition of amorphous calcium phosphate that matures over time, transforms into crystalline hydroxyapatite, and radiates towards the lumen of the vesicles, finally forming the calcified spherules. Elemental and mineralogical analyses also demonstrate that the presence of mature and stable amorphous calcium phosphate deposits in the affected tissues is linked to the incorporation of magnesium, which probably delay the conversion to the crystalline phase. Though more rarely, the presence of calcium oxalate crystals has been also documented.

Keywords

atherosclerosisvascular calcificationelectron microscopymatrix vesicles
Type
Biological Science Applications
Information
Microscopy and Microanalysis , Volume 23 , Issue 5 , October 2017 , pp. 1030 - 1039
Copyright
© Microscopy Society of America 2017 

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References

Alves, R.D., Eijken, M., van de Peppel, J. & van Leeuwen, J.P. (2014). Calcifying vascular smooth muscle cells and osteoblasts: Independent cell types exhibiting extracellular matrix and biomineralization-related mimicries. BMC Genomics 15, 965.CrossRefGoogle ScholarPubMed
Anderson, H.C. (1983). Calcific diseases. A concept. Arch Pathol Lab Med 107, 341–348.Google ScholarPubMed
Anderson, H.C. (2003). Matrix vesicles and calcification. Curr Rheumatol Rep 5, 222–226.CrossRefGoogle ScholarPubMed
Arbus, G.S. & Sniderman, S. (1974). Oxalosis with peripheral gangrene. Arch Pathol 97, 107–110.Google ScholarPubMed
Beniash, E., Metzler, R.A., Lam, R.S. & Gilbert, P.U. (2009). Transient amorphous calcium phosphate in forming enamel. J Struct Biol 166, 133143.CrossRefGoogle ScholarPubMed
Bertazzo, S., Gentleman, E., Cloyd, K.L., Chester, A.H., Yacoub, M.H. & Stevens, M.M. (2013). Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat Mater 12, 576–583.Google Scholar
Blumenthal, N.C., Betts, F. & Posner, A.S. (1977). Stabilization of amorphous calcium phosphate by Mg and ATP. Calcif Tissue Res 23, 245–250.Google Scholar
Bobryshev, Y.V., Killingsworth, M.C., Huynh, T.G., Lord, R.S., Grabs, A.J. & Valenzuela, S.M. (2007). Are calcifying matrix vesicles in atherosclerotic lesions of cellular origin? Basic Res Cardiol 102, 133–143.CrossRefGoogle ScholarPubMed
Bobryshev, Y.V., Killingsworth, M.C., Lord, R.S.A. & Grabse, A.J. (2008). Matrix vesicles in the fibrous cap of atherosclerotic plaque: Possible contribution to plaque rupture. J Cell Mol Med 12, 2073–2082.CrossRefGoogle ScholarPubMed
Boskey, A.L. & Posner, A.S. (1974). Magnesium stabilization of amorphous calcium phosphate: A kinetic study. Mater Res Bull 9, 907–916.CrossRefGoogle Scholar
Bostrom, K., Watson, K.E., Horn, S., Wortham, C., Herman, I.M. & Demer, L.L. (1993). Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 91, 1800–1809.Google Scholar
Chen, N.X., O’Neill, K.D., Chen, X. & Moe, S.M. (2008). Annexin-mediated matrix vesicle calcification in vascular smooth muscle cells. J Bone Miner Res 23, 1798–1805.CrossRefGoogle ScholarPubMed
Coltart, D.J. & Hudson, R.E. (1971). Primary oxalosis of the heart: A cause of heart block. Br Heart J 33, 315–319.Google Scholar
Cui, L., Houston, D.A., Farquharson, C. & MacRae, V.E. (2016). Characterisation of matrix vesicles in skeletal and soft tissue mineralisation. Bone 87, 147–158.CrossRefGoogle ScholarPubMed
Demer, L.L. & Tintut, Y. (2001). Vascular calcification. Pathobiology of a multifaceted disease. Circulation 104, 1881–1883.CrossRefGoogle Scholar
Doherty, T.M., Asotra, K., Fitzpatrick, L.A., Qiao, J.H., Wilkin, D.J., Detrano, R.C., Dunstan, C.R., Shah, P.K. & Rajavashisth, T.B. (2003). Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A 100, 11201–11206.Google Scholar
Doherty, T.M. & Detrano, R.C. (1994). Coronary arterial calcification as an active process: A new perspective on an old problem. Calcif Tissue Int 54, 224–230.Google Scholar
Duer, M.J., Friscić, T., Proudfoot, D., Reid, D.G., Schoppet, M., Shanahan, C.M., Skepper, J.N. & Wise, E.R. (2008). Mineral surface in calcified plaque is like that of bone: Further evidence for regulated mineralization. Arterioscler Thromb Vasc Biol 28, 2030–2034.CrossRefGoogle ScholarPubMed
Fishbein, G.A., Micheletti, R.G., Currier, J.S., Singer, E. & Fishbein, M.C. (2008). Atherosclerotic oxalosis in coronary arteries. Cardiovasc Pathol 17, 117–123.CrossRefGoogle ScholarPubMed
Fitzpatrick, L.A., Severson, A., Edwards, W.D. & Ingram, R.T. (1994). Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis. J Clin Invest 94, 1597–1604.Google Scholar
Galkina, E. & Ley, K. (2009). Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 27, 165–197.CrossRefGoogle ScholarPubMed
Gawoski, J.M., Balogh, K. & Landis, W.J. (1985). Aortic valvular tophus: Identification by X-ray diffraction of urate and calcium phosphates. J Clin Pathol 38, 873–876.CrossRefGoogle ScholarPubMed
Giachelli, C.M. (1999). Ectopic calcification. Gathering hard facts about soft tissue mineralization. Am J Pathol 154, 671–675.Google Scholar
Guasti, L., Marino, F., Congiu, C., Tozzi, M., Schembri, L., Maio, R.C., Castiglioni, L., Maroni, L., Castelli, P., Quacci, D.E., Dell’Orbo, C., Grandi, A.M., Lecchini, S., Cosentino, M. & Venco, A. (2010). Laminar pattern of mineral calcium-phosphorus deposits in a human carotid plaque: Nanoscale ultrastructure and elemental analysis. Circulation 121, 1971–1973.CrossRefGoogle Scholar
Kani, T., Kani, M., Moriwaki, Y. & Doi, Y. (1983). Microbeam x-ray diffraction analysis of dental calculus. J Dent Res 62, 92–95.CrossRefGoogle ScholarPubMed
Kim, K.M. (1976). Calcification of matrix vesicles in human aortic valve and aortic media. Fed Proc 35, 156–162.Google ScholarPubMed
Kodaka, T., Mori, R., Hirayama, A. & Sano, T. (2003). Fine structure and mineral components of fibrous stonelike masses obtained from the human mesenteries. Med Electron Microsc 36, 272–281.Google Scholar
Krohn, J.B., Hutcheson, J.D., Martínez-Martínez, E. & Aikawa, E. (2016). Extracellular vesicles in cardiovascular calcification: Expanding current paradigms. J Physiol 594, 2895–2903.Google Scholar
Lagier, R. & Baud, C.A. (2003). Magnesium whitlockite, a calcium phosphate crystal of special interest in pathology. Pathol Res Pract 199, 329–335.CrossRefGoogle Scholar
Li, Q., Jiang, Q. & Uitto, J. (2014). Ectopic mineralization disorders of the extracellular matrix of connective tissue: Molecular genetics and pathomechanisms of aberrant calcification. Matrix Biol 33, 23–28.Google Scholar
Liu, W., Zhang, Y., Yu, C.M., Ji, Q.W., Cai, M., Zhao, Y.X. & Zhou, Y.J. (2015). Current understanding of coronary artery calcification. J Geriatr Cardiol 12, 668–675.Google ScholarPubMed
Lorenz, E.C., Michet, C.J., Milliner, D.S. & Lieske, J.C. (2013). Update on oxalate crystal disease. Curr Rheumatol Rep 15, 340–356.CrossRefGoogle ScholarPubMed
Louvet, L., Bazin, D., Büchel, J., Steppan, S., Passlick-Deetjen, J. & Massy, Z.A. (2015). Characterisation of calcium phosphate crystals on calcified human aortic vascular smooth muscle cells and potential role of magnesium. PLoS One 10, e0115342.CrossRefGoogle ScholarPubMed
Mackey, R.H., Venkitachalam, L. & Sutton-Tyrrell, K. (2007). Calcifications, arterial stiffness and atherosclerosis. Adv Cardiol 44, 234–244.Google Scholar
Montel, G., Bonel, G., Heughebaert, J.C., Trombe, J.C. & Rey, C. (1981). New concepts in the composition, crystallization and growth of the mineral component of calcified tissues. J Crystal Growth 53, 74–99.Google Scholar
Nandalur, K.R., Hardie, A.D., Raghavan, P., Schipper, M.J., Baskurt, E. & Kramer, C.M. (2007). Composition of the stable carotid plaque: Insights from a multidetector computed tomography study of plaque volume. Stroke 38, 935–940.Google Scholar
New, S.E., Goettsch, C., Aikawa, M., Marchini, J.F., Shibasaki, M., Yabusaki, K., Libby, P., Shanahan, C.M., Croce, K. & Aikawa, E. (2013). Macrophage-derived matrix vesicles: An alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res 113, 72–77.CrossRefGoogle ScholarPubMed
Pan, H., Liu, X.Y., Tang, R. & Xu, H.Y. (2010). Mystery of the transformation from amorphous calcium phosphate to hydroxyapatite. Chem Commun 46, 7415–7417.CrossRefGoogle ScholarPubMed
Perrotta, I. (2017). Interaction between lipid droplets and endoplasmic reticulum in human atherosclerotic plaques. Ultrastruct Pathol 41, 1–9.CrossRefGoogle ScholarPubMed
Przewłocki, T., Kabłak-Ziembicka, A., Kozanecki, A., Rzeźnik, D., Pieniazek, P., Musiałek, P., Piskorz, A., Sokołowski, A., Rosławiecka, A. & Tracz, W. (2009). Polyvascular extracoronary atherosclerotic disease in patients with coronary artery disease. Kardiol Pol 67, 978–984.Google ScholarPubMed
Reid, J.D. & Andersen, M.E. (1993). Medial calcification (whitlockite) in the aorta. Atherosclerosis 101, 213–224.CrossRefGoogle ScholarPubMed
Reid, D.G., Shanahan, C.M., Duer, M.J., Arroyo, L.G., Schoppet, M., Brooks, R.A. & Murray, R.C. (2012). Lipids in biocalcification: Contrasts and similarities between intimal and medial vascular calcification and bone by NMR. J Lipid Res 53, 1569–1575.Google Scholar
Reschen, M.E., Lin, D., Chalisey, A., Soilleux, E.J. & O’Callaghan, C.A. (2016). Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1. Atherosclerosis 250, 95–105.Google Scholar
Sage, A.P., Tintut, Y. & Demer, L.L. (2010). Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 7, 528–536.CrossRefGoogle ScholarPubMed
Sakae, T. & Yamamoto, H. (1987). Crystals and calcification patterns in two lymph node calcifications. J Oral Pathol 16, 456–462.Google Scholar
Schembri, L., Congiu, T., Tozzi, M., Guasti, L., Cosentino, M. & Marino, F. (2008). Scanning electron microscopy examination and elemental analysis of atherosclerotic calcifications in a human carotid plaque. Circulation 117, e479–e480.Google Scholar
Schlieper, G., Aretz, A., Verberckmoes, S.C., Krüger, T., Behets, G.J., Ghadimi, R., Weirich, T.E., Rohrmann, D., Langer, S., Tordoir, J.H., Amann, K., Westenfeld, R., Brandenburg, V.M., D’Haese, P.C., Mayer, J., Ketteler, M., McKee, M.D. & Floege, J. (2010). Ultrastructural analysis of vascular calcifications in uremia. J Am Soc Nephrol 21, 689–696.Google Scholar
Shanahan, C.M. (2013). Autophagy and matrix vesicles: New partners in vascular calcification. Kidney Int 83, 984–986.CrossRefGoogle ScholarPubMed
Singh, R.B., Mengi, S.A., Xu, Y.J., Arneja, A.S. & Dhalla, N.S. (2002). Pathogenesis of atherosclerosis: A multifactorial process. Exp Clin Cardiol 7, 40–53.Google Scholar
Speer, M.Y., Yang, H.Y., Brabb, T., Leaf, E., Look, A., Lin, W.L., Frutkin, A., Dichek, D. & Giachelli, C.M. (2009). Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res 104, 733–741.Google Scholar
Stary, H.C., Chandler, A.B., Dinsmore, R.E., Fuster, V., Glagov, S., Insull, W. Jr, Rosenfeld, M.E., Schwartz, C.J., Wagner, W.D. & Wissler, R.W. (1995). A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92, 1355–1374.Google Scholar
Tanimura, A., McGregor, D.H. & Anderson, H.C. (1983). Matrix vesicles in atherosclerotic calcification. Proc Soc Exp Biol Med 172, 173–177.CrossRefGoogle ScholarPubMed
Tomazic, B.B. (2001). Physiochemical principles of cardiovascular calcification. Z Kardiol 3, 68–80.Google Scholar
Verberckmoes, S.C., Persy, V., Behets, G.J., Neven, E., Hufkens, A., Zebger-Gong, H., Müller, D., Haffner, D., Querfeld, U., Bohic, S., De Broe, M.E. & D’Haese, P.C. (2007). Uremia-related vascular calcification: More than apatite deposition. Kidney Int 71, 298–303.CrossRefGoogle ScholarPubMed
Wallin, R., Wajih, N., Greenwood, G.T. & Sane, D.C. (2001). Arterial calcification: A review of mechanisms, animal models, and the prospects for therapy. Med Res Rev 21, 274–301.CrossRefGoogle ScholarPubMed
Zhao, J., Liu, Y., Sun, W. & Yang, X. (2012). First detection, characterization, and application of amorphous calcium phosphate in dentistry. J Dent Sci 7, 316–323.Google Scholar