Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use

Circulation Research

Volumn 110, Issue 4, 2012, Pages 624-637

  Fadini, Gian Paolo ^a   Losordo, Douglas ^b,c   Dimmeler, Stefanie ^d  

^a VENETIAN INSTITUTE OF MOLECULAR MEDICINE   (Italy)

^b NORTHWESTERN UNIVERSITY   (United States)

^c BAXTER HEALTHCARE CORPORATION   (United States)

^d GOETHE UNIVERSITY   (Germany)

Author keywords

angiogenesis; endothelial progenitor cells; progenitor cells; risk factor; stem cells

Indexed keywords

BIOLOGICAL MARKER; CD133 ANTIGEN; CD34 ANTIGEN; MEMBRANE ANTIGEN;

CARDIOVASCULAR DISEASE; CELL CULTURE; CELL SUBPOPULATION; CELL THERAPY; CLINICAL EVALUATION; DIAGNOSTIC PROCEDURE; ENDOTHELIAL PROGENITOR CELL; FLUORESCENCE ACTIVATED CELL SORTER; HUMAN; NONHUMAN; PHENOTYPE; PREVALENCE; PRIORITY JOURNAL; PROGNOSIS; QUANTITATIVE ANALYSIS; REVIEW; RISK FACTOR;

ANIMALS; BIOLOGICAL MARKERS; CARDIOVASCULAR DISEASES; CELL CULTURE TECHNIQUES; CELL LINEAGE; CELL SEPARATION; ENDOTHELIAL CELLS; FLOW CYTOMETRY; HUMANS; IMMUNOPHENOTYPING; PHENOTYPE; PREDICTIVE VALUE OF TESTS; STEM CELL TRANSPLANTATION; STEM CELLS; TREATMENT OUTCOME;

EID: 84857604290     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.111.243386     Document Type: Review

References (157)

1. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964-967.
2. Ingram DA, Caplice NM, Yoder MC. Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood. 2005;106:1525-1531.
3. Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature. Atherosclerosis. 2010;209:10-17.
4. Lipinski MJ, Biondi-Zoccai GG, Abbate A, Khianey R, Sheiban I, Bartunek J, Vanderheyden M, Kim HS, Kang HJ, Strauer BE, Vetrovec GW. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol. 2007;50:1761-1767.
5. Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of myocardial infarction. Arterioscler Thromb Vasc Biol. 2008;28:208-216.
6. Fadini GP, Baesso I, Albiero M, Sartore S, Agostini C, Avogaro A. Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau. Atherosclerosis. 2008;197:496-503.
7. Urbich C, Heeschen C, Aicher A, Dernbach E, Zeiher AM, Dimmeler S. Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation. 2003;108:2511-2516.
8. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000;97:3422-3427.
9. Lopez-Holgado N, Alberca M, Sanchez-Guijo F, Villaron E, Almeida J, Martin A, Armellini A, Garcia C, Blanco B, Sanchez-Abarca I, Martin S, Perez-Simon JA, Garcia-Sanz R, San Miguel JF, Del Canizo MC. Short-term endothelial progenitor cell colonies are composed of monocytes and do not acquire endothelial markers. Cytotherapy. 2007;9:14-22.
10. Prokopi M, Pula G, Mayr U, Devue C, Gallagher J, Xiao Q, Boulanger CM, Westwood N, Urbich C, Willeit J, Steiner M, Breuss J, Xu Q, Kiechl S, Mayr M. Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood. 2009;114:723-732.
11. Koyanagi M, Brandes RP, Haendeler J, Zeiher AM, Dimmeler S. Celltocell connection of endothelial progenitor cells with cardiac myocytes by nanotubes: a novel mechanism for cell fate changes? Circ Res. 2005;96:1039-1041.
12. Rechavi O, Erlich Y, Amram H, Flomenblit L, Karginov FV, Goldstein I, Hannon GJ, Kloog Y. Cell contact-dependent acquisition of cellular and viral nonautonomously encoded small rnas. Genes Dev. 2009;23:1971-1979.
13. Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G, Viltono L, Tetta C, Camussi G. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010;5:e11803.
14. Hosoda T, Zheng H, Cabral-da-Silva M, Sanada F, Ide-Iwata N, Ogorek B, Ferreira-Martins J, Arranto C, D'Amario D, Del Monte F, Urbanek K, D'Alessandro DA, Michler RE, Anversa P, Rota M, Kajstura J, Leri A. Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation. 2011;123:1287-1296.
15. Aliotta JM, Pereira M, Johnson KW, De Paz N, Dooner MS, Puente N, Ayala C, Brilliant K, Berz D, Lee D, Ramratnam B, McMillan PN, Hixson DC, Josic D, Quesenberry PJ. Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp Hematol. 2010;38:233-245.
16. Ohtani K, Vlachojannis GJ, Koyanagi M, Boeckel JN, Urbich C, Farcas R, Bonig H, Marquez VE, Zeiher AM, Dimmeler S. Epigenetic regulation of endothelial lineage committed genes in pro-angiogenic hematopoietic and endothelial progenitor cells. Circ Res. 2011;109:1219-1223.
17. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593-600.
18. Hur J, Yang HM, Yoon CH, Lee CS, Park KW, Kim JH, Kim TY, Kim JY, Kang HJ, Chae IH, Oh BH, Park YB, Kim HS. Identification of a novel role of t cells in postnatal vasculogenesis: characterization of endothelial progenitor cell colonies. Circulation. 2007;116:1671-1682.
19. Rohde E, Bartmann C, Schallmoser K, Reinisch A, Lanzer G, Linkesch W, Guelly C, Strunk D. Immune cells mimic the morphology of endothelial progenitor colonies in vitro. Stem Cells. 2006;24:357-367.
20. Rohde E, Malischnik C, Thaler D, Maierhofer T, Linkesch W, Lanzer G, Guelly C, Strunk D. Blood monocytes mimic endothelial progenitor cells. Stem Cells. 2006;24:357-367.
21. Rehman J, Li J, Parvathaneni L, Karlsson G, Panchal VR, Temm CJ, Mahenthiran J, March KL. Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells. J Am Coll Cardiol. 2004;43:2314-2318.
22. Guven H, Shepherd RM, Bach RG, Capoccia BJ, Link DC. The number of endothelial progenitor cell colonies in the blood is increased in patients with angiographically significant coronary artery disease. J Am Coll Cardiol. 2006;48:1579-1587.
23. Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, Oh BH, Lee MM, Park YB. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol. 2004;24:288-293.
24. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2007;109:1801-1809.
25. Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K, Pollok K, Ferkowicz MJ, Gilley D, Yoder MC. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood. 2004;104:2752-2760.
26. Meneveau N, Deschaseaux F, Seronde MF, Chopard R, Schiele F, Jehl J, Tiberghien P, Bassand JP, Kantelip JP, Davani S. Presence of endothelial colony-forming cells is associated with reduced microvascular obstruction limiting infarct size and left ventricular remodelling in patients with acute myocardial infarction. Basic Res Cardiol. 2011;106:1397-1410.
27. Wang CH, Hsieh IC, Su Pang JH, Cherng WJ, Lin SJ, Tung TH, Mei HF. Factors associated with purity, biological function, and activation potential of endothelial colony-forming cells. Am J Physiol Regul Integr Comp Physiol. 2011;300:R586-R594.
28. Reinisch A, Hofmann NA, Obenauf AC, Kashofer K, Rohde E, Schallmoser K, Flicker K, Lanzer G, Linkesch W, Speicher MR, Strunk D. Humanized large-scale expanded endothelial colony-forming cells function in vitro and in vivo. Blood. 2009;113:6716-6725.
29. Case J, Mead LE, Bessler WK, Prater D, White HA, Saadatzadeh MR, Bhavsar JR, Yoder MC, Haneline LS, Ingram DA. Human cd34+ac133+vegfr-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors. Exp Hematol. 2007;35:1109-1118.
30. Masuda H, Alev C, Akimaru H, Ito R, Shizuno T, Kobori M, Horii M, Ishihara T, Isobe K, Isozaki M, Itoh J, Itoh Y, Okada Y, McIntyre BA, Kato S, Asahara T. Methodological development of a clonogenic assay to determine endothelial progenitor cell potential. Circ Res. 2011;109:20-37.
31. Gunetti M, Noghero A, Molla F, Staszewsky LI, de Angelis N, Soldo A, Russo I, Errichiello E, Frasson C, Rustichelli D, Ferrero I, Gualandris A, Berger M, Geuna M, Scacciatella P, Basso G, Marra S, Bussolino F, Latini R, Fagioli F. Ex vivo-expanded bone marrow cd34 (+) for acute myocardial infarction treatment: In vitro and in vivo studies. Cytotherapy. 2011;13:1140-1152.
32. Yang J, Ii M, Kamei N, Alev C, Kwon SM, Kawamoto A, Akimaru H, Masuda H, Sawa Y, Asahara T. Cd34+ cells represent highly functional endothelial progenitor cells in murine bone marrow. PLoS One. 2011;6:e20219.
33. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95:343-353.
34. Yoon CH, Hur J, Park KW, Kim JH, Lee CS, Oh IY, Kim TY, Cho HJ, Kang HJ, Chae IH, Yang HK, Oh BH, Park YB, Kim HS. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation. 2005;112:1618-1627.
35. Di Santo S, Yang Z, Wyler von Ballmoos M, Voelzmann J, Diehm N, Baumgartner I, Kalka C. Novel cell-free strategy for therapeutic angiogenesis: in vitro generated conditioned medium can replace progenitor cell transplantation. PLoS One. 2009;4:e5643.
36. Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, Dimmeler S. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005;39:733-742.
37. Rehman J, Li J, Orschell CM, March KL. Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation. 2003;107:1164-1169.
38. Heil M, Ziegelhoeffer T, Mees B, Schaper W. A different outlook on the role of bone marrow stem cells in vascular growth: bone marrow delivers software not hardware. Circ Res. 2004;94:573-574.
39. Deb A, Patterson C. Hard luck stories: The reality of endothelial progenitor cells continues to fall short of the promise. Circulation. 2010;121:850-852.
40. Hagensen MK, Raarup MK, Mortensen MB, Thim T, Nyengaard JR, Falk E, Bentzon JF. Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury. [epub ahead of print Nov. 7]. Cardiovasc Res. 2011.
41. Hagensen MK, Shim J, Falk E, Bentzon JF. Flanking recipient vasculature, not circulating progenitor cells, contributes to endothelium and smooth muscle in murine allograft vasculopathy. Arterioscler Thromb Vasc Biol. 2011;31:808-813.
42. Wickersheim A, Kerber M, de Miguel LS, Plate KH, Machein MR. Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors. Int J Cancer. 2009;125:1771-1777.
43. Sieveking DP, Buckle A, Celermajer DS, Ng MK. Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay. J Am Coll Cardiol. 2008;51:660-668.
44. Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C, Uchida S, Masuo O, Iwaguro H, Ma H, Hanley A, Silver M, Kearney M, Losordo DW, Isner JM, Asahara T. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation. 2003;107:461-468.
45. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic 634 Circulation Research February 17, 2012 myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7:430-436.
46. Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009;324:1710-1713.
47. Rajantie I, Ilmonen M, Alminaite A, Ozerdem U, Alitalo K, Salven P. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood. 2004;104:2084-2086.
48. De Palma M, Venneri MA, Galli R, Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8:211-226.
49. Fadini GP, Albiero M, Boscaro E, Agostini C, Avogaro A. Endothelial progenitor cells as resident accessory cells for post-ischemic angiogenesis. Atherosclerosis. 2009;204:20-22.
50. Ziebart T, Yoon CH, Trepels T, Wietelmann A, Braun T, Kiessling F, Stein S, Grez M, Ihling C, Muhly-Reinholz M, Carmona G, Urbich C, Zeiher AM, Dimmeler S. Sustained persistence of transplanted proangiogenic cells contributes to neovascularization and cardiac function after ischemia. Circ Res. 2008;103:1327-1334.
51. Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M, Schuch G, Schafhausen P, Mende T, Kilic N, Kluge K, Schafer B, Hossfeld DK, Fiedler W. In vitro differentiation of endothelial cells from ac133-positive progenitor cells. Blood. 2000;95:3106-3112.
52. Kawamoto A, Iwasaki H, Kusano K, Murayama T, Oyamada A, Silver M, Hulbert C, Gavin M, Hanley A, Ma H, Kearney M, Zak V, Asahara T, Losordo DW. Cd34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation. 2006;114:2163-2169.
53. Ramos AL, Darabi R, Akbarloo N, Borges L, Catanese J, Dineen SP, Brekken RA, Perlingeiro RC. Clonal analysis reveals a common progenitor for endothelial, myeloid, and lymphoid precursors in umbilical cord blood. Circ Res. 2010;107:1460-1469.
54. Pozzoli O, Vella P, Iaffaldano G, Parente V, Devanna P, Lacovich M, Lamia CL, Fascio U, Longoni D, Cotelli F, Capogrossi MC, Pesce M. Endothelial fate and angiogenic properties of human cd34+ progenitor cells in zebrafish. Arterioscler Thromb Vasc Biol. 2011;31:1589-1597.
55. Madeddu P, Emanueli C, Pelosi E, Salis MB, Cerio AM, Bonanno G, Patti M, Stassi G, Condorelli G, Peschle C. Transplantation of low dose cd34+kdr+ cells promotes vascular and muscular regeneration in ischemic limbs. FASEB J. 2004;18:1737-1739.
56. Friedrich EB, Walenta K, Scharlau J, Nickenig G, Werner N. Cd34-/cd133+/vegfr-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circ Res. 2006;98:e20-25.
57. Schmidt-Lucke C, Fichtlscherer S, Aicher A, Tschope C, Schultheiss HP, Zeiher AM, Dimmeler S. Quantification of circulating endothelial progenitor cells using the modified ishage protocol. PLoS One. 2010;5:e13790.
58. Seeger FH, Rasper T, Koyanagi M, Fox H, Zeiher AM, Dimmeler S. Cxcr4 expression determines functional activity of bone marrow-derived mononuclear cells for therapeutic neovascularization in acute ischemia. Arterioscler Thromb Vasc Biol. 2009.
59. Kim SW, Kim H, Cho HJ, Lee JU, Levit R, Yoon YS. Human peripheral blood-derived cd31+ cells have robust angiogenic and vasculogenic properties and are effective for treating ischemic vascular disease. J Am Coll Cardiol. 2010;56:593-607.
60. Kim H, Cho HJ, Kim SW, Liu B, Choi YJ, Lee J, Sohn YD, Lee MY, Houge MA, Yoon YS. Cd31+ cells represent highly angiogenic and vasculogenic cells in bone marrow: novel role of nonendothelial cd31+ cells in neovascularization and their therapeutic effects on ischemic vascular disease. Circ Res. 2010;107:602-614.
61. Goldie LC, Nix MK, Hirschi KK. Embryonic vasculogenesis and hematopoietic specification. Organogenesis. 2008;4:257-263.
62. Bailey AS, Jiang S, Afentoulis M, Baumann CI, Schroeder DA, Olson SB, Wong MH, Fleming WH. Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood. 2004;103:13-19.
63. Gunsilius E, Duba HC, Petzer AL, Kahler CM, Grunewald K, Stockhammer G, Gabl C, Dirnhofer S, Clausen J, Gastl G. Evidence from a leukaemia model for maintenance of vascular endothelium by bonemarrowderived endothelial cells. Lancet. 2000;355:1688-1691.
64. Chao H, Hirschi KK. Hemato-vascular origins of endothelial progenitor cells? Microvasc Res. 2010;79:169-173.
65. Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G. The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature. 2009;457:892-895.
66. Puato M, Faggin E, Favaretto E, Bertipaglia B, Rattazzi M, Rizzoni D, Gamba GP, Sartore S, Rosei EA, Pessina AC, Pauletto P. Prevalence of fetal-type smooth muscle cells in the media of microvessels from hypertensive patients. Hypertension. 2004;44:191-194.
67. Mercola M, Ruiz-Lozano P, Schneider MD. Cardiac muscle regeneration: lessons from development. Genes Dev. 2011;25:299-309.
68. Zape JP, Zovein AC. Hemogenic endothelium: origins, regulation, and implications for vascular biology. Semin Cell Dev Biol. 2011;22:1036-1047.
69. Blann AD, Woywodt A, Bertolini F, Bull TM, Buyon JP, Clancy RM, Haubitz M, Hebbel RP, Lip GY, Mancuso P, Sampol J, Solovey A, Dignat-George F. Circulating endothelial cells. Biomarker of vascular disease. Thromb Haemost. 2005;93:228-235.
70. Mancuso P, Antoniotti P, Quarna J, Calleri A, Rabascio C, Tacchetti C, Braidotti P, Wu HK, Zurita AJ, Saronni L, Cheng JB, Shalinsky DR, Heymach JV, Bertolini F. Validation of a standardized method for enumerating circulating endothelial cells and progenitors: flow cytometry and molecular and ultrastructural analyses. Clin Cancer Res. 2009;15:267-273.
71. Hristov M, Erl W, Weber PC. Endothelial progenitor cells: isolation and characterization. Trends Cardiovasc Med. 2003;13:201-206.
72. Povsic TJ, Zavodni KL, Kelly FL, Zhu S, Goldschmidt-Clermont PJ, Dong C, Peterson ED. Circulating progenitor cells can be reliably identified on the basis of aldehyde dehydrogenase activity. J Am Coll Cardiol. 2007;50:2243-2248.
73. Leor J, Marber M. Endothelial progenitors: a new tower of Babel? J Am Coll Cardiol. 2006;48:1588-1590.
74. Heiss C, Keymel S, Niesler U, Ziemann J, Kelm M, Kalka C. Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol. 2005;45:1441-1448.
75. Fadini GP, de Kreutzenberg S, Albiero M, Coracina A, Pagnin E, Baesso I, Cignarella A, Bolego C, Plebani M, Nardelli GB, Sartore S, Agostini C, Avogaro A. Gender differences in endothelial progenitor cells and cardiovascular risk profile: the role of female estrogens. Arterioscler Thromb Vasc Biol. 2008;28:997-1004.
76. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001;89:E1-E7.
77. Bulut D, Tuns H, Mugge A. Cd31+/annexin v+ microparticles in healthy offsprings of patients with coronary artery disease. Eur J Clin Invest. 2009;39:17-22.
78. Humpert PM, Neuwirth R, Battista MJ, Voronko O, von Eynatten M, Konrade I, Rudofsky G Jr, Wendt T, Hamann A, Morcos M, Nawroth PP, Bierhaus A. Sdf-1 genotype influences insulin-dependent mobilization of adult progenitor cells in type 2 diabetes. Diabetes Care. 2005;28:934-936.
79. Kondo T, Hayashi M, Takeshita K, Numaguchi Y, Kobayashi K, Iino S, Inden Y, Murohara T. Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. Arterioscler Thromb Vasc Biol. 2004;24:1442-1447.
80. Di Stefano R, Barsotti MC, Felice F, Magera A, Lekakis J, Leone A, Balbarini A. Smoking and endothelial progenitor cells: a revision of literature. Curr Pharm Des. 2010;16:2559-2566.
81. Ludwig A, Jochmann N, Kertesz A, Kuhn C, Mueller S, Gericke C, Baumann G, Stangl K, Stangl V. Smoking decreases the level of circulating cd34+ progenitor cells in young healthy women-a pilot study. BMC Womens Health. 2010;10:20.
82. Yue WS, Wang M, Yan GH, Yiu KH, Yin L, Lee SW, Siu CW, Tse HF. Smoking is associated with depletion of circulating endothelial progenitor cells and elevated pulmonary artery systolic pressure in patients with coronary artery disease. Am J Cardiol. 2010;106:1248-1254.
83. Michaud SE, Dussault S, Haddad P, Groleau J, Rivard A. Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities. Atherosclerosis. 2006;187:423-432.
84. Pirro M, Schillaci G, Menecali C, Bagaglia F, Paltriccia R, Vaudo G, Mannarino MR, Mannarino E. Reduced number of circulating endothelial progenitors and hoxa9 expression in cd34+ cells of hypertensive patients. J Hypertens. 2007;25:2093-2099.
85. Oliveras A, Soler MJ, Martinez-Estrada OM, Vazquez S, Marco-Feliu D, Vila JS, Vilaro S, Lloveras J. Endothelial progenitor cells are reduced in refractory hypertension. J Hum Hypertens. 2008;22:183-190.
86. Umemura T, Soga J, Hidaka T, Takemoto H, Nakamura S, Jitsuiki D, Nishioka K, Goto C, Teragawa H, Yoshizumi M, Chayama K, Higashi Y. Aging and hypertension are independent risk factors for reduced number of circulating endothelial progenitor cells. Am J Hypertens. 2008;21:1203-1209.
87. Giannotti G, Doerries C, Mocharla PS, Mueller MF, Bahlmann FH, Horvath T, Jiang H, Sorrentino SA, Steenken N, Manes C, Marzilli M, Rudolph KL, Luscher TF, Drexler H, Landmesser U. Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: relation to endothelial dysfunction. Hypertension. 2010;55:1389-1397.
88. Delva P, Degan M, Vallerio P, Arosio E, Minuz P, Amen G, Di Chio M, Lechi A. Endothelial progenitor cells in patients with essential hypertension. J Hypertens. 2007;25:127-132.
89. Yang Z, Chen L, Su C, Xia WH, Wang Y, Wang JM, Chen F, Zhang YY, Wu F, Xu SY, Zhang XL, Tao J. Impaired endothelial progenitor cell activity is associated with reduced arterial elasticity in patients with essential hypertension. Clin Exp Hypertens. 2010;32:444-452.
90. Lee CW, Huang PH, Huang SS, Leu HB, Huang CC, Wu TC, Chen JW, Lin SJ. Decreased circulating endothelial progenitor cell levels and function in essential hypertensive patients with electrocardiographic left ventricular hypertrophy. Hypertens Res. 2011.
91. Rossi F, Bertone C, Montanile F, Miglietta F, Lubrano C, Gandini L, Santiemma V. HDL cholesterol is a strong determinant of endothelial progenitor cells in hypercholesterolemic subjects. Microvasc Res. 2010;80:274-279.
92. Chen JZ, Zhang FR, Tao QM, Wang XX, Zhu JH. Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. Clin Sci (Lond). 2004;107:273-280.
93. Heida NM, Muller JP, Cheng IF, Leifheit-Nestler M, Faustin V, Riggert J, Hasenfuss G, Konstantinides S, Schafer K. Effects of obesity and weight loss on the functional properties of early outgrowth endothelial progenitor cells. J Am Coll Cardiol. 2010;55:357-367.
94. Tobler K, Freudenthaler A, Baumgartner-Parzer SM, Wolzt M, Ludvik B, Nansalmaa E, Nowotny PJ, Seidinger D, Steiner S, Luger A, Artwohl M. Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity. Int J Obes (Lond). 2010;34:687-700.
95. Muller-Ehmsen J, Braun D, Schneider T, Pfister R, Worm N, Wielckens K, Scheid C, Frommolt P, Flesch M. Decreased number of circulating progenitor cells in obesity: beneficial effects of weight reduction. Eur Heart J. 2008;29:1560-1568.
96. Egan CG, Lavery R, Caporali F, Fondelli C, Laghi-Pasini F, Dotta F, Sorrentino V. Generalised reduction of putative endothelial progenitors and cxcr4-positive peripheral blood cells in type 2 diabetes. Diabetologia. 2008;51:1296-1305.
97. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004;53:195-199.
98. Fadini GP, Pucci L, Vanacore R, Baesso I, Penno G, Balbarini A, Di Stefano R, Miccoli R, de Kreutzenberg S, Coracina A, Tiengo A, Agostini C, Del Prato S, Avogaro A. Glucose tolerance is negatively associated with circulating progenitor cell levels. Diabetologia. 2007;50:2156-2163.
99. Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A, Agostini C, Avogaro A. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol. 2005;45:1449-1457.
100. Seeger FH, Haendeler J, Walter DH, Rochwalsky U, Reinhold J, Urbich C, Rossig L, Corbaz A, Chvatchko Y, Zeiher AM, Dimmeler S. p38 mitogen-activated protein kinase downregulates endothelial progenitor cells. Circulation. 2005;111:1184-1191.
101. Zhu J, Wang X, Chen J, Sun J, Zhang F. Reduced number and activity of circulating endothelial progenitor cells from patients with hyperhomocysteinemia. Arch Med Res. 2006;37:484-489.
102. Makino H, Okada S, Nagumo A, Sugisawa T, Miyamoto Y, Kishimoto I, Kikuchi-Taura A, Soma T, Taguchi A, Yoshimasa Y. Decreased circulating cd34+ cells are associated with progression of diabetic nephropathy. Diabet Med. 2009;26:171-173.
103. George J, Goldstein E, Abashidze S, Deutsch V, Shmilovich H, Finkelstein A, Herz I, Miller H, Keren G. Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation. Eur Heart J. 2004;25:1003-1008.
104. Dei Cas A, Spigoni V, Ardigo D, Pedrazzi G, Franzini L, Derlindati E, Urbani S, Monti L, Gnudi L, Zavaroni I. Reduced circulating endothelial progenitor cell number in healthy young adult hyperinsulinemic men. Nutr Metab Cardiovasc Dis. 2011;21:512-517.
105. Fadini GP, Agostini C, Boscaro E, Avogaro A. Mechanisms and significance of progenitor cell reduction in the metabolic syndrome. Metab Syndr Relat Disord. 2009;7:5-10.
106. Fadini GP, de Kreutzenberg SV, Coracina A, Baesso I, Agostini C, Tiengo A, Avogaro A. Circulating cd34+ cells, metabolic syndrome, and cardiovascular risk. Eur Heart J. 2006;27:2247-2255.
107. Bahlmann FH, de Groot K, Mueller O, Hertel B, Haller H, Fliser D. Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension. 2005;45:526-529.
108. Benndorf RA, Gehling UM, Appel D, Maas R, Schwedhelm E, Schlagner K, Silberhorn E, Hossfeld DK, Rogiers X, Boger R. Mobilization of putative high-proliferative-potential endothelial colonyforming cells during antihypertensive treatment in patients with essential hypertension. Stem Cells Dev. 2007;16:329-338.
109. Fadini GP, de Kreutzenberg SV, Mariano V, Boscaro E, Bertolini F, Mancuso P, Quarna J, Marescotti M, Agostini C, Tiengo A, Avogaro A. Optimized glycaemic control achieved with add-on basal insulin therapy improves indexes of endothelial damage and regeneration in type 2 diabetic patients with macroangiopathy: a randomized crossover trial comparing detemir versus glargine. Diabetes Obes Metab. 2011;13:718-725.
110. Fadini GP, Avogaro A. Potential manipulation of endothelial progenitor cells in diabetes and its complications. Diabetes Obes Metab. 2010;12:570-583.
111. Ramunni A, Brescia P, Dambra P, Capuzzimati L, Ria R, De Tullio G, Resta F, Russi G, Vacca A, Coratelli P. Effect of low-density lipoprotein apheresis on circulating endothelial progenitor cells in familial hypercholesterolemia. Blood Purif. 2010;29:383-389.
112. Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001;103:2885-2890.
113. Fadini GP, Agostini C, Sartore S, Avogaro A. Endothelial progenitor cells in the natural history of atherosclerosis. Atherosclerosis. 2007;194:46-54.
114. Huang PH, Chen YH, Chen YL, Wu TC, Chen JW, Lin SJ. Vascular endothelial function and circulating endothelial progenitor cells in patients with cardiac syndrome X. Heart. 2007;93:1064-1070.
115. Fadini GP, Pagano C, Baesso I, Kotsafti O, Doro D, de Kreutzenberg SV, Avogaro A, Agostini C, Dorigo MT. Reduced endothelial progenitor cells and brachial artery flow-mediated dilation as evidence of endothelial dysfunction in ocular hypertension and primary open-angle glaucoma. Acta Ophthalmol. 2010;88:135-141.
116. Esposito K, Ciotola M, Maiorino MI, Giugliano F, Autorino R, De Sio M, Jannini E, Lenzi A, Giugliano D. Circulating cd34+ kdr+ endothelial progenitor cells correlate with erectile function and endothelial function in overweight men. J Sex Med. 2009;6:107-114.
117. Sibal L, Aldibbiat A, Agarwal SC, Mitchell G, Oates C, Razvi S, Weaver JU, Shaw JA, Home PD. Circulating endothelial progenitor cells, endothelial function, carotid intima-media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria. Diabetologia. 2009;52:1464-1473.
118. Mok MY, Yiu KH, Wong CY, Qiuwaxi J, Lai WH, Wong WS, Tse HF, Lau CS. Low circulating level of cd133+kdr+cells in patients with systemic sclerosis. Clin Exp Rheumatol. 2010;28:S19-S25.
119. Calo LA, Facco M, Davis PA, Pagnin E, Maso LD, Puato M, Caielli P, Agostini C, Pessina AC. Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin ii signaling. Hypertens Res. 2011.
120. Fadini GP, Coracina A, Baesso I, Agostini C, Tiengo A, Avogaro A, de Kreutzenberg SV. Peripheral blood cd34+kdr+ endothelial progenitor cells are determinants of subclinical atherosclerosis in a middle-aged general population. Stroke. 2006;37:2277-2282.
121. Chironi G, Walch L, Pernollet MG, Gariepy J, Levenson J, Rendu F, Simon A. Decreased number of circulating cd34+kdr+ cells in asymptomatic subjects with preclinical atherosclerosis. Atherosclerosis. 2007;191:115-120.
122. Bielak LF, Horenstein RB, Ryan KA, Sheedy PF, Rumberger JA, Tanner K, Post W, Mitchell BD, Shuldiner AR, Peyser PA. Circulating cd34+ cell count is associated with extent of subclinical atherosclerosis in asymptomatic Amish men, independent of 10-year Framingham risk. Clin Med Cardiol. 2009;3:53-60.
123. Kunz GA, Liang G, Cuculi F, Gregg D, Vata KC, Shaw LK, Goldschmidt-Clermont PJ, Dong C, Taylor DA, Peterson ED. Circulating endothelial progenitor cells predict coronary artery disease severity. Am Heart J. 2006;152:190-195.
124. Wang HY, Gao PJ, Ji KD, Shen WF, Fan CL, Lu L, Zhu DL. Circulating endothelial progenitor cells, C-reactive protein and severity of coronary stenosis in Chinese patients with coronary artery disease. Hypertens Res. 2007;30:133-141.
125. Fadini GP, Sartore S, Albiero M, Baesso I, Murphy E, Menegolo M, Grego F, Vigili de Kreutzenberg S, Tiengo A, Agostini C, Avogaro A. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol. 2006;26:2140-2146.
126. Lau KK, Chan YH, Yiu KH, Li SW, Tam S, Lau CP, Kwong YL, Tse HF. Burden of carotid atherosclerosis in patients with stroke: relationships with circulating endothelial progenitor cells and hypertension. J Hum Hypertens. 2007;21:445-451.
127. Bogoslovsky T, Chaudhry A, Latour L, Maric D, Luby M, Spatz M, Frank J, Warach S. Endothelial progenitor cells correlate with lesion volume and growth in acute stroke. Neurology. 2010;75:2059-2062.
128. Hughes AD, Coady E, Raynor S, Mayet J, Wright AR, Shore AC, Kooner JS, Thom SA, Chaturvedi N. Reduced endothelial progenitor cells in European and South Asian men with atherosclerosis. Eur J Clin Invest. 2007;37:35-41.
129. Ghani U, Shuaib A, Salam A, Nasir A, Shuaib U, Jeerakathil T, Sher F, O'Rourke F, Nasser AM, Schwindt B, Todd K. Endothelial progenitor cells during cerebrovascular disease. Stroke. 2005;36:151-153.
130. Xiao Q, Kiechl S, Patel S, Oberhollenzer F, Weger S, Mayr A, Metzler B, Reindl M, Hu Y, Willeit J, Xu Q. Endothelial progenitor cells, cardiovascular risk factors, cytokine levels and atherosclerosis: results from a large population-based study. PLoS One. 2007;2:e975.
131. Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation. 2001;103:2776-2779.
132. Leone AM, Rutella S, Bonanno G, Abbate A, Rebuzzi AG, Giovannini S, Lombardi M, Galiuto L, Liuzzo G, Andreotti F, Lanza GA, Contemi AM, Leone G,
133. Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, De Ferrari GM, Ferlini M, Goffredo L, Bertoletti A, Klersy C, Pecci A, Moratti R, Tavazzi L. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood. 2005;105:199-206.
134. Sobrino T, Hurtado O, Moro MA, Rodriguez-Yanez M, Castellanos M, Brea D, Moldes O, Blanco M, Arenillas JF, Leira R, Davalos A, Lizasoain I, Castillo J. The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke. 2007;38:2759-2764.
135. Yip HK, Chang LT, Chang WN, Lu CH, Liou CW, Lan MY, Liu JS, Youssef AA, Chang HW. Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke. 2008;39:69-74.
136. Bogoslovsky T, Spatz M, Chaudhry A, Maric D, Luby M, Frank J, Warach S. Stromal-derived factor-1+ correlates with circulating endothelial progenitor cells and with acute lesion volume in stroke patients. Stroke. 2011;42:618-625.
137. Aicher A, Zeiher AM, Dimmeler S. Mobilizing endothelial progenitor cells. Hypertension. 2005;45:321-325.
138. Kuliczkowski W, Derzhko R, Prajs I, Podolak-Dawidziak M, Serebruany VL. Endothelial progenitor cells and left ventricle function in patients with acute myocardial infarction: potential therapeutic considerations. Am J Ther. 2010.
139. Fadini GP. Is bone marrow another target of diabetic complications? Eur J Clin Invest. 2011;41:457-463.
140. Andreou I, Tousoulis D, Tentolouris C, Antoniades C, Stefanadis C. Potential role of endothelial progenitor cells in the pathophysiology of heart failure: clinical implications and perspectives. Atherosclerosis. 2006;189:247-254.
141. Valgimigli M, Rigolin GM, Fucili A, Porta MD, Soukhomovskaia O, Malagutti P, Bugli AM, Bragotti LZ, Francolini G, Mauro E, Castoldi G, Ferrari R. Cd34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation. 2004;110:1209-1212.
142. Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-Rasokat U, Heeschen C, Spyridopoulos I, Dimmeler S, Zeiher AM. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol. 2007;49:2341-2349.
143. Fritzenwanger M, Lorenz F, Jung C, Fabris M, Thude H, Barz D, Figulla HR. Differential number of cd34+, cd133+ and cd34+/cd133+ cells in peripheral blood of patients with congestive heart failure. Eur J Med Res. 2009;14:113-117.
144. Gatta L, Armani A, Iellamo F, Consoli C, Molinari F, Caminiti G, Volterrani M, Rosano GM. Effects of a short-term exercise training on serum factors involved in ventricular remodelling in chronic heart failure patients. [epub ahead of print Nov. 19]. Int J Cardiol. 2010.
145. Erbs S, Hollriegel R, Linke A, Beck EB, Adams V, Gielen S, Mobius-Winkler S, Sandri M, Krankel N, Hambrecht R, Schuler G. Exercise training in patients with advanced chronic heart failure (NYHA IIIB) promotes restoration of peripheral vasomotor function, induction of endogenous regeneration, and improvement of left ventricular function. Circ Heart Fail. 2010;3:486-494.
146. Van Craenenbroeck EM, Bruyndonckx L, Van Berckelaer C, Hoymans VY, Vrints CJ, Conraads VM. The effect of acute exercise on endothelial progenitor cells is attenuated in chronic heart failure. Eur J Appl Physiol. 2011;111:2375-2379.
147. Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, Kamper U, Dimmeler S, Zeiher AM. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005;111:2981-2987.
148. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999-1007.
149. Maruyama S, Taguchi A, Iwashima S, Ozaki T, Yasuda K, Kikuchi-Taura A, Soma T, Ishii H, Murohara T, Takahashi H, Kasuga H, Kumada Y, Toriyama T, Ito Y, Kawahara H, Yuzawa Y, Matsuo S. Low circulating cd34+ cell count is associated with poor prognosis in chronic hemodialysis patients. Kidney Int. 2008;74:1603-1609.
150. Lorenzen J, David S, Bahlmann FH, de Groot K, Bahlmann E, Kielstein JT, Haller H, Fliser D. Endothelial progenitor cells and cardiovascular events in patients with chronic kidney disease: a prospective follow-up study. PLoS One. 2010;5:e11477.
151. Fadini GP, de Kreutzenberg S, Agostini C, Boscaro E, Tiengo A, Dimmeler S, Avogaro A. Low cd34+ cell count and metabolic syndrome synergistically increase the risk of adverse outcomes. Atherosclerosis. 2009;207:213-219.
152. Fadini GP, Maruyama S, Ozaki T, Taguchi A, Meigs J, Dimmeler S, Zeiher AM, de Kreutzenberg S, Avogaro A, Nickenig G, Schmidt-Lucke C, Werner N. Circulating progenitor cell count for cardiovascular risk stratification: a pooled analysis. PLoS One. 2010;5:e11488.
153. Zethelius B, Berglund L, Sundstrom J, Ingelsson E, Basu S, Larsson A, Venge P, Arnlov J. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med. 2008;358:2107-2116.
154. Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, Angelici L, Masson S, Mohammed SA, Dejana E, Gorini M, Zeiher AM, Latini R. Levels of circulating pro-angiogenic cells predict cardiovascular outcomes in patients with chronic heart failure. J Card Fail. 2009;15:747-755.
155. Schwartzenberg S, Afek A, Charach G, Rubinstein A, Ben-Shoshan Y, Kissil S, Maisel-Auslender S, Keren G, George J. Comparative analysis of the predictive power of different endothelial progenitor cell phenotypes on cardiovascular outcome. World J Cardiol. 2010;2:299-304.
156. Porto I, Leone AM, De Maria GL, Craig CH, Tritarelli A, Camaioni C, Natale L, Niccoli G, Biasucci LM, Crea F. Are endothelial progenitor cells mobilized by myocardial ischemia or myocardial necrosis? A cardiac magnetic resonance study. Atherosclerosis. 2011;216:355-358.
157. Schober A, Hristov M, Kofler S, Forbrig R, Lohr B, Heussen N, Zhe Z, Akhtar S, Schumann U, Krotz F, Leibig M, Konig A, Kaczmarek I, Reichart B, Klauss V, Weber C, Sohn HY. Cd34+cd140b+ cells and circulating cxcl12 correlate with the angiographically assessed severity of cardiac allograft vasculopathy. Eur Heart J. 2011;32:476-484.