Title: Vascular Smooth Muscle Cells in the Pathogenesis of Vascular Calcification
Abstract: HomeCirculation ResearchVol. 104, No. 6Vascular Smooth Muscle Cells in the Pathogenesis of Vascular Calcification Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBVascular Smooth Muscle Cells in the Pathogenesis of Vascular Calcification Keith A. Hruska Keith A. HruskaKeith A. Hruska From the Department of Pediatrics, Renal Division, Washington University School of Medicine, St Louis, Mo. Search for more papers by this author Originally published27 Mar 2009https://doi.org/10.1161/CIRCRESAHA.109.195487Circulation Research. 2009;104:710–711Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. In atherosclerotic lesions, calcification is mainly found in the neointima of atheromatous plaques and has been shown to positively correlate with the plaque burden and the risk of myocardial infarction. Calcification of atherosclerotic plaques has been clearly shown to result from osteoblastic differentiation of cells in the neointima forming a mineralized matrix-containing type I collagen similar to bone formation.1–3 The origin of the neointimal osteoblastic cells remains controversial, but evidence that they derive from migratory smooth muscle cells is growing. Atherosclerotic calcification is increased by chronic kidney disease, type 2 diabetes mellitus, and aging.However, another form of vascular calcification, that of the vascular media, known as Mönckeberg’s medial calcific sclerosis, is also prevalent in patients with chronic kidney disease, in type 2 diabetes mellitus, and in aging patients, especially those with osteoporosis. Medial calcification in these patients can occur independently of intimal atherosclerotic lesions and features linear calcium phosphate deposits along the elastic lamellae, which may form circumferential mineral deposits throughout the media. Medial calcification causes vascular stiffness and increased pulse wave velocity that causes cardiac dysfunction/ischemia. Mineralization of elastin is clearly different from osteoblastic bone formation, and the pathogenesis of medial calcification is less clear than that of atherosclerosis. Osteochondroblastic differentiation has been detected in cells adjacent to medial calcific deposits along with type II collagen in the matrix.4In 1997, Luo et al reported the important finding of diffuse medial calcification with aortic rupture and death between 6 to 8 weeks of age in mice deficient of the matrix gla protein (MGP).5 The vascular calcification in MGP−/− mice affected the elastic lamellae of elastic and muscular arteries, such as aortas, carotids, and coronary arteries. Calcification in these mice was associated with profound changes in cell differentiation as arterial smooth muscle cells (SMCs) were replaced by chondrocyte-like cells undergoing progressive mineralization. MGP−/− mice are not atherosclerotic. MGP is a calcification inhibitor that accumulates at the border of calcified areas and in normal media of blood vessels and appears to act locally to limit calcium phosphate deposition in the vessel wall. The calcium-binding function of MGP requires vitamin K-dependent γ-carboxylation for activation, and undercarboxylated MGP, mainly resulting from vitamin K insufficiency and/or long-term warfarin treatment, accelerates the development of vascular calcification. In addition, polymorphisms of the MGP gene are associated with an increased risk of myocardial infarction, as well as cardiovascular mortality in chronic kidney disease and hemodialysis patients. Mutation of the MGP gene causes excessive arterial calcification in the human autosomal recessive condition Keutel syndrome.In this issue of Circulation Research, Speer et al6 attempt to provide definitive evidence that SMCs contribute to the origin of osteochondroblastic cells seen in calcified blood vessels by a fate mapping approach in MGP−/− mice. They bred transgenic mice carrying a SM22-cre transgene and mice carrying the R26R-LacZ transgene into the MGP−/− background. The result of Cre recombinase activity in mice bearing both transgenes is β-galactosidase activity detected by blue staining in cells expressing SM22. Blue-stained cells of MGP mice were limited to smooth muscle-rich tissue, such as the arterial media, and, importantly, the bone marrow was negative. In MGP−/− mice, β-galactosidase-positive cells resembling chondrocytes apparently secreting osteopontin and type II collagen were involved in large calcific medial lesions. The chondrocytic cells were not positive for smooth muscle myosin heavy chain, SM22α, or SMα actin, although they had previously expressed SM22 because they were β-galactosidase-positive. This provides the strong suggestion that the chondrocytic cells had differentiated from SMCs. This is the exciting contribution of this report. Evidence to support circulating or resident multipotent mesenchymal progenitors as the source of the chondrocytic cells was lacking, though not definitive. The time course of expression of Runx2 in the arterial media demonstrated expression in β-galactosidase positive, SM22α-positive medial cells at 2 weeks of age before calcification. After 2 weeks of age, Runx2 and SM22α expression decrease as chondrocytic calcifying cells appear. Because Runx2 is critical for both the chondrocytic and osteoblastic lineage, a weakness of this report is that Sox 9 expression, specific for chondrocytic cells, was not similarly characterized. However, another critical osteoblastic transcription factor, osterix, was not expressed in the MGP−/− arteries.An important issue not addressed by Speer et al6 is whether or not the vascular calcification of the MGP−/− mice is a model of Mönckeberg’s medial calcific sclerosis. From the calcific lesions shown in the report, calcification along the elastic lamellae was clearly evident in agreement with Luo et al, albeit at an older age (4 weeks compared to 2 to 3 weeks). However, the presence of chondrocytic cells was limited to larger lesions, and the sections shown in the report bearing chondrocytic cells demonstrate organization into large calcified lesions. Chondrocytic cells were not evident along the elastic lamellae calcifications, raising the issue of whether MGP−/− deficiency is a model of Mönckeberg’s medial calcific sclerosis and whether the latter is caused by chondrocytic cells mineralizing a type II collagen matrix as in the large lesions of the MGP−/− mouse. Thus, the nature of Mönckeberg’s medial calcific sclerosis remains an unsolved issue.Speer et al, when attempting to characterize potential mechanisms of the SMC transdifferentiation that they discovered in the MGP−/− mice, analyzed a vascular SMC culture system. The weakness of the in vitro system is that it is not a model of the in vivo situation, and the relationship of their in vitro findings to their animal model is not clear. Vascular smooth muscle cells in culture can differentiate along the osteoblastic lineage, as confirmed by Speer et al, but they did not achieve the chondrocytic differentiation and the absence of terminal osteoblastic differentiation shown by lack of osterix expression that they found in their MGP−/− mice. Speer et al did not analyze the action of MGP−/− deficiency in stimulating chondrocytic transdifferentiation of SMC, although they allude to the possibility that its role may be to bind bone morphogenetic protein-2 in the extracellular matrix, thereby inhibiting bone morphogenetic protein-2 function as an osteochondrogenic morphogen and osteoinductive factor.In summary, the report by Speer et al establishes that arterial SMCs developing normally in utero transdifferentiate along the chondrocytic lineage in the first few weeks of postnatal life in MGP−/− mice. This leads to calcification of large chondrocytic cell bearing medial lesions. In addition, the MGP−/− mice have calcification of elastic lamellae, in which the presence of the chondrocytic cells is not apparent. Thus, the relationship of the chondrocytic differentiation of SMCs to calcification of elastic lamellae in Mönckeberg’s medial calcific sclerosis is not established by this report, although a role of MGP deficiency is suggested.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingSupported by NIH grants DK070790 and AR41677.DisclosuresNone.FootnotesCorrespondence to Dr Keith A. Hruska, Professor of Pediatrics, Medicine and Cell Biology, Department of Pediatrics, Renal Division, Washington University School of Medicine, Campus Box 8208 5109 MPRB Building, 660 S Euclid, St Louis, MO 63110-1026. E-mail [email protected] References 1 Al-Aly Z, Shao JS, Lai CF, Huang E, Cai J, Behrmann A, Cheng SL, Towler DA. Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr−/− mice. Arterioscler Thromb Vasc Biol. 2007; 27: 2589–2596.LinkGoogle Scholar2 Mathew S, Tustison KS, Sugatani T, Chaudhary LR, Rifas L, Hruska KA. The mechanism of phosphorus as a cardiovascular risk factor in chronic kidney disease. J Am Soc Nephrol. 2008; 19: 1092–1105.CrossrefMedlineGoogle Scholar3 Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004; 24: 1161–1170.LinkGoogle Scholar4 Shanahan CM, Cary NRB, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation. 1999; 100: 2168–2176.CrossrefMedlineGoogle Scholar5 Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997; 386: 78–81.CrossrefMedlineGoogle Scholar6 Speer MY, Yang H-Y, Brabb T, Leaf E, Look A, Lin W-L, Frutkin A, Dichek D, Giachelli CM. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res. 2009; 104: 733–741.LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Wang D and Wang X (2022) Diosgenin and Its Analogs: Potential Protective Agents Against Atherosclerosis, Drug Design, Development and Therapy, 10.2147/DDDT.S368836, Volume 16, (2305-2323) Sekaran S, Vimalraj S and Thangavelu L (2021) The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization, Biomolecules, 10.3390/biom11111564, 11:11, (1564) Yang X, Chen A, Liang Q, Dong Q, Fu M, Liu X, Wang S, Li Y, Ye Y, Lan Z, Ou J, Lu L and Yan J (2021) Up-regulation of heme oxygenase-1 by celastrol alleviates oxidative stress and vascular calcification in chronic kidney disease, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2021.06.020, 172, (530-540), Online publication date: 1-Aug-2021. Grijalva-Guiza R, Jiménez-Garduño A and Hernández L (2021) Potential Benefits of Flavonoids on the Progression of Atherosclerosis by Their Effect on Vascular Smooth Muscle Excitability, Molecules, 10.3390/molecules26123557, 26:12, (3557) Chen Y, Zhao X and Wu H (2020) Arterial Stiffness, Arteriosclerosis, Thrombosis, and Vascular Biology, 40:5, (1078-1093), Online publication date: 1-May-2020.Liu L, Zeng P, Yang X, Duan Y, Zhang W, Ma C, Zhang X, Yang S, Li X, Yang J, Liang Y, Han H, Zhu Y, Han J and Chen Y (2018) Inhibition of Vascular Calcification, Arteriosclerosis, Thrombosis, and Vascular Biology, 38:10, (2382-2395), Online publication date: 1-Oct-2018. Sun W, Wang N and Xu Y (2018) Impact of miR-302b on Calcium-phosphorus Metabolism and Vascular Calcification of Rats with Chronic Renal Failure by Regulating BMP-2/Runx2/Osterix Signaling Pathway, Archives of Medical Research, 10.1016/j.arcmed.2018.08.002, 49:3, (164-171), Online publication date: 1-Apr-2018. Díaz Coronado J, Uribe S, González M, Giraldo C and Zuluaga M (2017) Clinical manifestations of Monckeberg's sclerosis. Report of case and literature review, Revista Colombiana de Reumatología (English Edition), 10.1016/j.rcreue.2017.09.002, 24:2, (118-122), Online publication date: 1-Apr-2017. Díaz Coronado J, Herrera Uribe S, González M, Posada Giraldo C and Mejía Zuluaga M (2017) Manifestaciones clínicas de la esclerosis de Monckeberg. Reporte de caso y revisión de la literatura, Revista Colombiana de Reumatología, 10.1016/j.rcreu.2016.12.004, 24:2, (118-122), Online publication date: 1-Apr-2017. Liu Y, Lin F, Fu Y, Chen W, Liu W, Chi J, Zhang X and Yin X (2016) Cortistatin inhibits calcification of vascular smooth muscle cells by depressing osteoblastic differentiation and endoplasmic reticulum stress, Amino Acids, 10.1007/s00726-016-2303-3, 48:11, (2671-2681), Online publication date: 1-Nov-2016. Yang R, Teng X, Li H, Xue H, Guo Q, Xiao L and Wu Y (2016) Hydrogen Sulfide Improves Vascular Calcification in Rats by Inhibiting Endoplasmic Reticulum Stress, Oxidative Medicine and Cellular Longevity, 10.1155/2016/9095242, 2016, (1-9), . Li N, Cheng W, Huang T, Yuan J, Wang X, Song M and Miller F (2015) Vascular Adventitia Calcification and Its Underlying Mechanism, PLOS ONE, 10.1371/journal.pone.0132506, 10:7, (e0132506) Leopold J (2014) MicroRNAs Regulate Vascular Medial Calcification, Cells, 10.3390/cells3040963, 3:4, (963-980) Giallauria F, Vigorito C, Ferrara N and Ferrucci L (2013) Cardiovascular Calcifications in Old Age: Mechanisms and Clinical Implications, Current Translational Geriatrics and Experimental Gerontology Reports, 10.1007/s13670-013-0063-4, 2:4, (255-267), Online publication date: 1-Dec-2013. Hampson G, Edwards S, Conroy S, Blake G, Fogelman I and Frost M (2013) The relationship between inhibitors of the Wnt signalling pathway (Dickkopf-1(DKK1) and sclerostin), bone mineral density, vascular calcification and arterial stiffness in post-menopausal women, Bone, 10.1016/j.bone.2013.05.010, 56:1, (42-47), Online publication date: 1-Sep-2013. Hajhosseiny R, Khavandi K and Goldsmith D (2012) Cardiovascular disease in chronic kidney disease: untying the Gordian knot, International Journal of Clinical Practice, 10.1111/j.1742-1241.2012.02954.x, 67:1, (14-31), Online publication date: 1-Jan-2013. Li X, Guo Y, Ziegler K, Model L, Eghbalieh S, Brenes R, Kim S, Shu C and Dardik A (2011) Current Usage and Future Directions for the Bovine Pericardial Patch, Annals of Vascular Surgery, 10.1016/j.avsg.2010.11.007, 25:4, (561-568), Online publication date: 1-May-2011. Li X, Guo Y, Ziegler K, Model L, Eghbalieh S, Brenes R, Kim S, Shu C and Dardik A (2011) Utilisations actuelles et futures des patchs péricardiques bovins, Annales de Chirurgie Vasculaire, 10.1016/j.acvfr.2012.04.019, 25:4, (603-610), Online publication date: 1-May-2011. Hruska K, Mathew S, Lund R, Fang Y and Sugatani T (2011) Cardiovascular risk factors in chronic kidney disease: does phosphate qualify?, Kidney International, 10.1038/ki.2011.24, 79, (S9-S13), Online publication date: 1-Apr-2011. Bobryshev Y, Tran D, Botelho N, Lord R and Orekhov A (2011) Musashi-1 expression in atherosclerotic arteries and its relevance to the origin of arterial smooth muscle cells: Histopathological findings and speculations, Atherosclerosis, 10.1016/j.atherosclerosis.2011.01.013, 215:2, (355-365), Online publication date: 1-Apr-2011. Maor E, Ivorra A, Mitchell J and Rubinsky B (2010) Vascular Smooth Muscle Cells Ablation with Endovascular Nonthermal Irreversible Electroporation, Journal of Vascular and Interventional Radiology, 10.1016/j.jvir.2010.06.024, 21:11, (1708-1715), Online publication date: 1-Nov-2010. Doehring L, Heeger C, Aherrahrou Z, Kaczmarek P, Erdmann J, Schunkert H and Ehlers E (2010) Myeloid CD34+CD13+ Precursor Cells Transdifferentiate into Chondrocyte-Like Cells in Atherosclerotic Intimal Calcification, The American Journal of Pathology, 10.2353/ajpath.2010.090758, 177:1, (473-480), Online publication date: 1-Jul-2010. Maciel T, Kempf H and Campos A (2010) Targeting bone morphogenetic protein signaling on renal and vascular diseases, Current Opinion in Nephrology and Hypertension, 10.1097/MNH.0b013e328332fc13, 19:1, (26-31), Online publication date: 1-Jan-2010. March 27, 2009Vol 104, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.109.195487PMID: 19325156 Originally publishedMarch 27, 2009 Keywordsosteoblast differentiationvascular calcificationvascular smooth muscle cellschondrocyte differentiationmatrix Gla proteinPDF download Advertisement