Abstract
Background:
The balance between endothelial injury and repair in childhood is poorly understood. We examined this relationship in healthy children, in adults, and in children with familial hypercholesterolemia (FH).
Methods:
Circulating endothelial cells (CECs) were measured as a marker of vascular injury, with vascular repair assessed by counting colony-forming units (CFUs), also known as endothelial progenitor cells.
Results:
CEC number increased with age. Children with FH had elevated CECs as compared with healthy children, with similar levels numerically to those found in healthy adults. CFU numbers were higher in healthy children than either healthy adults or children with FH. Endothelium-dependent vascular function, measured by flow-mediated dilatations, was positively associated with CFU number, even after adjustment for confounding risk variables.
Conclusion:
Levels of CECs increase and CFUs decrease with age. In childhood, before the onset of clinically detectable cardiovascular dysfunction, children with a major risk factor for atherosclerotic disease have levels of these indexes of vascular injury and repair approaching those seen in adults.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Grundy SM . Age as a risk factor: you are as old as your arteries. Am J Cardiol 1999;83:1455–7, A7.
Dawber TR . The Framingham Study: The Epidemiology of Atherosclerotic Disease. Cambridge, MA: Harvard University Press, 1980.
Clarke LA, Shah V, Arrigoni F, et al. Quantitative detection of circulating endothelial cells in vasculitis: comparison of flow cytometry and immunomagnetic bead extraction. J Thromb Haemost 2008;6:1025–32.
Deanfield J, Donald A, Ferri C, et al. Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005;23:7–17.
Järvisalo MJ, Jartti L, Näntö-Salonen K, et al. Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation 2001;104:2943–7.
Murray C, Lopez A . The World Health Report 2002: Reducing Risks, Promoting Healthy Life. Geneva, Switzerland: World Health Organization, 2002:230.
Virkola K, Pesonen E, Akerblom HK, Siimes MA . Cholesterol and carotid artery wall in children and adolescents with familial hypercholesterolaemia: a controlled study by ultrasound. Acta Paediatr 1997;86:1203–7.
Yoder MC, Mead LE, Prater D, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007;109:1801–9.
Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593–600.
Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005;353:999–1007.
Schmidt-Lucke C, Rössig L, Fichtlscherer S, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005;111:2981–7.
Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001;103:2885–90.
Imanishi T, Hano T, Matsuo Y, Nishio I . Oxidized low-density lipoprotein inhibits vascular endothelial growth factor-induced endothelial progenitor cell differentiation. Clin Exp Pharmacol Physiol 2003;30:665–70.
Imanishi T, Hano T, Sawamura T, Nishio I . Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clin Exp Pharmacol Physiol 2004;31:407–13.
Croce G, Passacquale G, Necozione S, Ferri C, Desideri G . Nonpharmacological treatment of hypercholesterolemia increases circulating endothelial progenitor cell population in adults. Arterioscler Thromb Vasc Biol 2006;26:e38–9.
Hoetzer GL, MacEneaney OJ, Irmiger HM, et al. Gender differences in circulating endothelial progenitor cell colony-forming capacity and migratory activity in middle-aged adults. Am J Cardiol 2007;99:46–8.
Jie KE, Goossens MH, van Oostrom O, Lilien MR, Verhaar MC . Circulating endothelial progenitor cell levels are higher during childhood than in adult life. Atherosclerosis 2009;202:345–7.
Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7.
Hirschi KK, Ingram DA, Yoder MC . Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008;28:1584–95.
Minami E, Laflamme MA, Saffitz JE, Murry CE . Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart. Circulation 2005;8:19.
Hagensen MK, Shim J, Thim T, Falk E, Bentzon JF . Circulating endothelial progenitor cells do not contribute to plaque endothelium in murine atherosclerosis. Circulation 2010;121:898–905.
Gulati R, Jevremovic D, Witt TA, et al. Modulation of the vascular response to injury by autologous blood-derived outgrowth endothelial cells. Am J Physiol Heart Circ Physiol 2004;287:H512–7.
Gehling UM, Ergün S, Fiedler W . CFU-EC: how they were originally defined. Blood 2007;110:1073.
Werner N, Wassmann S, Ahlers P, et al. Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease. Basic Res Cardiol 2007;102:565–71.
Fadini GP, Coracina A, Baesso I, et al. Peripheral blood CD34+KDR+ endothelial progenitor cells are determinants of subclinical atherosclerosis in a middle-aged general population. Stroke 2006;37:2277–82.
Westerweel PE, Visseren FL, Hajer GR, et al. Endothelial progenitor cell levels in obese men with the metabolic syndrome and the effect of simvastatin monotherapy vs. simvastatin/ezetimibe combination therapy. Eur Heart J 2008;29:2808–17.
Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 2002;106:2781–6.
Fadini GP, de Kreutzenberg S, Agostini C, et al. Low CD34+ cell count and metabolic syndrome synergistically increase the risk of adverse outcomes. Atherosclerosis 2009;207:213–9.
Woywodt A, Blann AD, Kirsch T, et al. Isolation and enumeration of circulating endothelial cells by immunomagnetic isolation: proposal of a definition and a consensus protocol. J Thromb Haemost 2006;4:671–7.
Bulut D, Tüns H, Mügge A . CD31+/Annexin V+ microparticles in healthy offsprings of patients with coronary artery disease. Eur J Clin Invest 2009;39:17–22.
Smadja DM, Gaussem P, Mauge L, et al. Circulating endothelial cells: a new candidate biomarker of irreversible pulmonary hypertension secondary to congenital heart disease. Circulation 2009;119:374–81.
Wiegman A, de Groot E, Hutten BA, et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet 2004;363:369–70.
Smilde TJ, van Wissen S, Wollersheim H, Kastelein JJ, Stalenhoef AF . Genetic and metabolic factors predicting risk of cardiovascular disease in familial hypercholesterolemia. Neth J Med 2001;59:184–95.
Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE . Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest 1994;93:50–5.
Walther C, Adams V, Bothur I, et al. Increasing physical education in high school students: effects on concentration of circulating endothelial progenitor cells. Eur J Cardiovasc Prev Rehabil 2008;15:416–22.
Reilly JJ, Methven E, McDowell ZC, et al. Health consequences of obesity. Arch Dis Child 2003;88:748–52.
Charakida M, Donald AE, Green H, et al. Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy. Circulation 2005;112:103–9.
Kari JA, Donald AE, Vallance DT, et al. Physiology and biochemistry of endothelial function in children with chronic renal failure. Kidney Int 1997;52:468–72.
Arrigoni FI, Matarin M, Thompson PJ, et al. Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy. Eur J Hum Genet 2011;19:131–7.
Donald AE, Halcox JP, Charakida M, et al. Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. J Am Coll Cardiol 2008;51:1959–64.
Acknowledgements
We thank the Vasculopathy Consortium at the Institute of Child Health, which helped with the endothelial assays and with patient recruitment.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fabbri-Arrigoni, F., Clarke, L., Wang, G. et al. Levels of circulating endothelial cells and colony-forming units are influenced by age and dyslipidemia. Pediatr Res 72, 299–304 (2012). https://doi.org/10.1038/pr.2012.76
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2012.76
This article is cited by
-
Impaired function of endothelial progenitor cells in children with primary systemic vasculitis
Arthritis Research & Therapy (2015)
-
Endothelial progenitor cells proliferated via MEK-dependent p42 MAPK signaling pathway
Molecular and Cellular Biochemistry (2015)
