CLINICAL RESEARCH: PROGENITOR CELLS
Circulating Endothelial Progenitor Cells Are Reduced in Peripheral Vascular Complications of Type 2 Diabetes Mellitus
Gian Paolo Fadini, MD*,*,
Marta Miorin, BS ,
Monica Facco, BS,
Sondra Bonamico,
Ilenia Baesso, BS,
Franco Grego, MD ,
Mirko Menegolo, MD,
Saula Vigili de Kreutzenberg, MD*,
Antonio Tiengo, MD*,
Carlo Agostini, MD and
Angelo Avogaro, MD, PhD*
* Department of Clinical and Experimental Medicine, Division of Metabolic Diseases, University of Padova, School of Medicine, Padova, Italy
Department of Clinical and Experimental Medicine, Clinical Immunology and Hematology, University of Padova, School of Medicine, Padova, Italy
Department of Medical and Surgical Sciences, Division of Vascular Surgery, University of Padova, School of Medicine, Padova, Italy
Manuscript received August 20, 2004;
revised manuscript received November 8, 2004,
accepted November 22, 2004.
* Reprint requests and correspondence: Dr. Gian Paolo Fadini, Department of Clinical and Experimental Medicine, University of Padova, School of Medicine, Via Giustiniani 2, 35128 Padova, Italy (Email: angelo.avogaro{at}unipd.it).
OBJECTIVES: We sought to establish whether a reduction in endothelial progenitor cells (EPCs) has a putative role in peripheral vascular disease (PVD) of type 2 diabetic patients.
BACKGROUND: Peripheral vascular disease is a common and severe complication of diabetes mellitus. Impaired collateralization of diabetic vasculopathy has been extensively shown, but causes leading to its pathogenesis are not fully understood. Recently, EPCs have been found to contribute to vascular repair and angiogenesis. Diabetes has been associated with low levels of circulating EPCs, but no data are available in the literature on the relationship between EPCs and PVD in diabetes.
METHODS: Flow cytometric analysis was used to quantify circulating progenitor cells (CPCs, CD34+) and EPCs (CD34+KDR+) in 51 patients and 17 control subjects.
RESULTS: The CPCs and EPCs from diabetic patients were reduced by 33% and 40%, respectively, compared with healthy subjects (p < 0.001). An inverse correlation was found between the number of EPCs and the values of fasting glucose (r = –0.49, p = 0.006). Peripheral vascular disease was associated with a 47% reduction in EPCs (p < 0.0001) and EPC levels directly correlated with the ankle-brachial index (r = 0.70, p = 0.01). The subgroup of diabetic patients with PVD also had reduced CPCs by 32% (p = 0.037), whereas patients with ischemic foot lesions had the lowest levels of both EPCs and CPCs (p = 0.02).
CONCLUSIONS: Our data demonstrate decreased EPC levels in diabetic patients and, for the first time, show that PVD is associated with an extensively low number of EPCs. Depletion of circulating EPCs in diabetic patients may be involved in the pathogenesis of peripheral vascular complications.
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Abbreviations and Acronyms
| | ABI = ankle-brachial index | | AER = albuminuria excretion rate | | CAD = coronary artery disease | | CPC = circulating progenitor cell | | DM = diabetes mellitus | | EPC = endothelial progenitor cell | | PVD = peripheral vascular disease |
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|
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|
|
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|
|
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|
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|
|
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|
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|
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|
|
|
|
|
|
|
S. Anwaruddin, A. T. Askari, and E. J. Topol
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|
|
|
|
|
|
|
S. Zhu, X. Liu, Y. Li, P. J. Goldschmidt-Clermont, and C. Dong
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|
|
|
|
|
|
|
G. C. Schatteman, M. Dunnwald, and C. Jiao
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292(1):
H1 - H18.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Avogaro and G. P. Fadini
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2561 - 2563.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Mieno, M. Boodhwani, R. T. Clements, B. Ramlawi, N. R. Sodha, J. Li, and F. W. Sellke
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132(6):
1348 - 1355.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Leor and M. Marber
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48(8):
1588 - 1590.
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|
|
|
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|
|
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G. P. Fadini, S. V. de Kreutzenberg, A. Coracina, I. Baesso, C. Agostini, A. Tiengo, and A. Avogaro
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27(18):
2247 - 2255.
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[Full Text]
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|
|
|
|
|
|
|
G. P. Fadini, A. Avogaro, and C. Agostini
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Am. J. Respir. Cell Mol. Biol.,
September 1, 2006;
35(3):
403 - 404.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Fadini, S. Sartore, M. Albiero, I. Baesso, E. Murphy, M. Menegolo, F. Grego, S. Vigili de Kreutzenberg, A. Tiengo, C. Agostini, et al.
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September 1, 2006;
26(9):
2140 - 2146.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Fadini, A. Coracina, I. Baesso, C. Agostini, A. Tiengo, A. Avogaro, and S. Vigili de Kreutzenberg
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September 1, 2006;
37(9):
2277 - 2282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Marchetti, R. Menghini, S. Rizza, A. Vivanti, T. Feccia, D. Lauro, A. Fukamizu, R. Lauro, and M. Federici
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August 1, 2006;
55(8):
2231 - 2237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Dome, J. Timar, J. Dobos, L. Meszaros, E. Raso, S. Paku, I. Kenessey, G. Ostoros, M. Magyar, A. Ladanyi, et al.
Identification and clinical significance of circulating endothelial progenitor cells in human non-small cell lung cancer.
Cancer Res.,
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66(14):
7341 - 7347.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Li, W. Shen, R. Gill, A. Corbly, B. Jones, R. Belagaje, Y. Zhang, S. Tang, Y. Chen, Y. Zhai, et al.
High-Resolution Quantitative Computed Tomography Demonstrating Selective Enhancement of Medium-Size Collaterals by Placental Growth Factor-1 in the Mouse Ischemic Hindlimb
Circulation,
May 23, 2006;
113(20):
2445 - 2453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Atluri, G. P. Liao, C. M. Panlilio, V. M. Hsu, M. J. Leskowitz, K. J. Morine, J. E. Cohen, M. F. Berry, E. E. Suarez, D. A. Murphy, et al.
Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy.
Ann. Thorac. Surg.,
May 1, 2006;
81(5):
1728 - 1736.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Fadini, S. Sartore, I. Baesso, M. Lenzi, C. Agostini, A. Tiengo, and A. Avogaro
Endothelial progenitor cells and the diabetic paradox.
Diabetes Care,
March 1, 2006;
29(3):
714 - 716.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Fadini and A. Avogaro
Autologous transplantation of granulocyte colony-stimulating factor- mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes.
Diabetes Care,
February 1, 2006;
29(2):
478 - 479.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, W. Y.W. Lew, D. Sahn, and S. Tsimikas
Highlights of the Year in JACC 2005
J. Am. Coll. Cardiol.,
January 3, 2006;
47(1):
184 - 202.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Dong, L. E. Crawford, and P. J. Goldschmidt-Clermont
Endothelial Progenitor Obsolescence and Atherosclerotic Inflammation
J. Am. Coll. Cardiol.,
May 3, 2005;
45(9):
1458 - 1460.
[Full Text]
[PDF]
|
|
|
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