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Endothelial progenitor cells and their potential clinical implication in cardiovascular disorders

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Abstract

Risk factors associated with cardiovascular diseases reduce the availability of endothelial progenitor cells (EPC) by affecting their mobilization and integration into injured vascular sites. The existence of a bone marrow reservoir of EPC has attracted interest, especially as target for therapeutic intervention in different pathological settings. Among the cardiovascular risk factors, hypertension has been shown to be a strongest predictor of EPC migratory impairment. However, at present, data concerning EPC biology are still limited. In this article we provide an overview of data relevant to their potential clinical implications in cardiovascular disorders. In addition, the recent advances in understanding the role of EPC in the pathophysiology of hypertension are discussed.

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References

  1. Drexler H, Hornig B. Endothelial dysfuction in human desease. J Mol Cell Cardiol 1999, 31: 51–60.

    PubMed  CAS  Google Scholar 

  2. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004, 15: 1983–92.

    PubMed  CAS  Google Scholar 

  3. Dimmeler S, Zeiher AM. Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis. J Mol Med 2004, 82: 671–7.

    PubMed  Google Scholar 

  4. Caplan BA, Schwartz CJ. Increased endothelial cell turnover in areas of in vivo Evans blue uptake in the pig aorta. Atherosclerosis 1973, 17: 401–17.

    PubMed  CAS  Google Scholar 

  5. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 2004, 95: 343–53.

    PubMed  CAS  Google Scholar 

  6. Rafil S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003, 9: 702–12.

    Google Scholar 

  7. Takahashi T, Kalka C, Masuda H, Chen D, et al. Ischemia- and cytokine-induced mobilization of bone-marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999, 5: 434–8.

    PubMed  CAS  Google Scholar 

  8. Kalka C, Tehrani H, Laudenberg B, et al. VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease. Ann Thorac Surg 2000, 70: 829–34.

    PubMed  CAS  Google Scholar 

  9. Shintani S, Murohara T, Ikeda H, et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001, 103: 2776–9.

    PubMed  CAS  Google Scholar 

  10. Kong D, Melo L, Gnecchi M, et al. Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation 2004, 110: 2039–46.

    PubMed  CAS  Google Scholar 

  11. Fujiyama S, Amano K, Uehira K, et al. Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells. Circ Res 2003, 93: 980–9.

    PubMed  CAS  Google Scholar 

  12. Werner N, Junk S, Laufs U, et al. Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res 2003, 93: e17–24.

    PubMed  CAS  Google Scholar 

  13. Griese DP, Ehsan A, Melo LG, et al. Isolation and transplantation of autologous circulating endothelial cells into denuded vessels and prosthetic grafts: implications for cell-based vascular therapy. Circulation 2003, 108: 2710–5.

    PubMed  Google Scholar 

  14. Kong D, Melo L, Mangi AA, et al. Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation 2004, 109: 1769–75.

    PubMed  CAS  Google Scholar 

  15. Iwaguro H, Yamaguchi J, Kalka C, et al. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 2002, 105: 732–8.

    PubMed  CAS  Google Scholar 

  16. Rauscher FM, Goldschmidt-Clermont P, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003, 108: 457–63.

    PubMed  Google Scholar 

  17. Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001, 89: E1–7.

    PubMed  CAS  Google Scholar 

  18. Hill JM, Zalos G, Halcox JPG, et al. Circulating endothelial progenitor cells, vascular function and cardiovascular risk. N Engl J Med 2003, 348: 593–600.

    PubMed  Google Scholar 

  19. Urbich C, Dimmeler S. Endothelial progenitor cells functional characterization. Trends Cardiovasc Med 2004, 14: 318–22.

    PubMed  CAS  Google Scholar 

  20. Masuda H, Asahara T. Post-natal endothelial progenitor cells for neovascularization and tissue regeneration. Cardiovasc Res 2003, 58: 390–8.

    PubMed  CAS  Google Scholar 

  21. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999, 85: 221–8.

    PubMed  CAS  Google Scholar 

  22. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002, 109: 337–46.

    PubMed Central  PubMed  CAS  Google Scholar 

  23. 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: 2511–6.

    PubMed  Google Scholar 

  24. Rehman J, Li J, Orschell CM, March KL. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic factors. Circulation 2003, 107: 1164–9.

    PubMed  Google Scholar 

  25. Asahara T, Murohara T, Sullivan A, et al. Isolation of putatitve progenitor endothelial cells for angiogenesis. Science 1997, 275: 964–7.

    PubMed  CAS  Google Scholar 

  26. Boyer M, Townsend L, Vogel LM, et al. Isolation of endothelial cells and their progenitor cells from human peripheral blood. J Vasc Surg 2000, 31: 181–9.

    PubMed  CAS  Google Scholar 

  27. Romagnani P, Annunziato F, Liotta F, et al. CD14+CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circ Res 2005, 97: 314–22.

    PubMed  CAS  Google Scholar 

  28. Kalka C, Masuda H, Takahashi T, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 2000, 97: 3422–7.

    PubMed Central  PubMed  CAS  Google Scholar 

  29. Kawamoto A, Gwon H-C, Iwaguro H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001, 103: 634–7.

    PubMed  CAS  Google Scholar 

  30. Kocher AA, Schuster M, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001, 7: 430–6.

    PubMed  CAS  Google Scholar 

  31. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999, 85: 221–8.

    PubMed  CAS  Google Scholar 

  32. Yamashita J, Itoh H, Hirashima M, et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 2000, 408: 92–6.

    PubMed  CAS  Google Scholar 

  33. Hur J, Yoon C, Kim HS, et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 2004, 24: 288–93.

    PubMed  CAS  Google Scholar 

  34. Gulati R, Jevremovic D, Peterson TE, et al. Diverse origin and function of cells with endothelial phenotype obtained from adult human blood. Circ Res 2003, 93: 1023–5.

    PubMed  CAS  Google Scholar 

  35. Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K. Identification of a novel hierarchy of endothelial progenitor cells using human peripherial and umbilical cord blood. Blood 2004, 104: 2752–60.

    PubMed  CAS  Google Scholar 

  36. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000, 105: 71–7.

    PubMed Central  PubMed  CAS  Google Scholar 

  37. Zeoli A, Dentelli P, Rosso A, et al. Interleukin-3 IL-3 promotes expansion of hemopoietic-derived CD45+ angiogenic cells and their arterial commitment via STAT5 activation. Blood 2008, 112: 350–61.

    PubMed  CAS  Google Scholar 

  38. Papayannopoulou T. Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 2004, 103: 1580–5.

    PubMed  CAS  Google Scholar 

  39. Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999, 18: 3964–72.

    PubMed Central  PubMed  CAS  Google Scholar 

  40. Askari AT, Unzek S, Popovic ZB, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003, 362: 697–703.

    PubMed  CAS  Google Scholar 

  41. Ceradini DJ, Kulkarni A, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004, 10: 858–64.

    PubMed  CAS  Google Scholar 

  42. Kalka C, Masuda H, Takahashi T, et al. Vascular endothelial growth factor (165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 2000, 86: 1198–202.

    PubMed  CAS  Google Scholar 

  43. Moore MA, Hattori K, Heissig B, et al. Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-1. Ann N Y Acad Sci 2001, 938: 36–47.

    PubMed  CAS  Google Scholar 

  44. Kalka C, Tehrani H, Laudenberg B, et al. VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease. Ann Thorac Surg 2000, 70: 829–34.

    PubMed  CAS  Google Scholar 

  45. Gill M, Dias S, Hattori K, et al. Vascular trauma induces rapid but transient mobilization of VEGFR2+AC133+ endothelial precursor cells. Circ Res 2001, 88: 167–74.

    PubMed  CAS  Google Scholar 

  46. Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 2001, 193: 1005–14.

    PubMed Central  PubMed  CAS  Google Scholar 

  47. Morimoto A, Sakata Y, Watanabe T, Murakami N. Leucocytosis induced in rabbits by intravenous or central injection of granulocyte colony stimulating factor. J Physiol 1990, 426: 117–26.

    PubMed Central  PubMed  CAS  Google Scholar 

  48. Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004, 363: 751–6.

    PubMed  CAS  Google Scholar 

  49. Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 2003, 102: 1340–6.

    PubMed  CAS  Google Scholar 

  50. Bahlmann FH, De Groot K, Spandau JM, et al. Erythropoietin regulates endothelial progenitor cells. Blood 2004, 103: 921–6.

    PubMed  CAS  Google Scholar 

  51. Flanagan JG, Chan DC, Leder P. Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell 1991, 4: 1025–35.

    Google Scholar 

  52. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002, 109: 625–37.

    PubMed Central  PubMed  CAS  Google Scholar 

  53. Lévesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003, 111: 187–96.

    PubMed Central  PubMed  Google Scholar 

  54. Hattori K, Heissig B, Tashiro K, et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 2001, 97: 3354–60.

    PubMed  CAS  Google Scholar 

  55. Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003, 9: 1370–6.

    PubMed  CAS  Google Scholar 

  56. Schenkel AR, Mamdouh Z, Muller WA. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 2004, 5: 393–400.

    PubMed  CAS  Google Scholar 

  57. de Boer HC, Verseyden C, Ulfman LH, et al. Fibrin and activated platelets cooperatively guide stem cells to a vascular injury and promote differentiation towards an endothelial cell phenotype. Arterioscler Thromb Vasc Biol 2006, 26: 1653–9.

    PubMed  Google Scholar 

  58. Chavakis E, Aicher A, Heeschen C, et al. Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 2005, 201: 63–72.

    PubMed Central  PubMed  CAS  Google Scholar 

  59. Yamaguchi J, Kusano KF, Masuo O, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003, 107: 1322–8.

    PubMed  CAS  Google Scholar 

  60. Rössig L, Urbich C, Brühl T, et al. Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells. J Exp Med 2005, 201: 1825–35.

    PubMed Central  PubMed  Google Scholar 

  61. Yamamoto K, Takahashi T, Asahara T, et al. Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress. J Appl Physiol 2003, 95: 2081–8.

    PubMed  Google Scholar 

  62. Dentelli P, Rosso A, Balsamo A, et al. C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium. Blood 2007, 109: 4264–71.

    PubMed  CAS  Google Scholar 

  63. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999, 340: 115–26.

    PubMed  CAS  Google Scholar 

  64. Schwartz SM, Benditt EP. Clustering of replicating cells in aortic endothelium. Proc Natl Acad Sci U S A 1976, 73: 651–3.

    PubMed Central  PubMed  CAS  Google Scholar 

  65. Op den Buijs J, Musters M, Verrips T, Post JA, Braam B, van Riel N. Mathematical modeling of vascular endothelial layer maintenance: the role of endothelial cell division, progenitor cell homing, and telomere shortening. Am J Physiol Heart Circ Physiol 2004, 287: H2651–8.

    Google Scholar 

  66. Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlates with risk factors for coronary artery disease. Circ Res 2001, 89: E1–7.

    PubMed  CAS  Google Scholar 

  67. Loomans CJ, de Koning EJ, Staal FJ, et al. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 2004, 53: 195–9.

    PubMed  CAS  Google Scholar 

  68. Tepper OM, Galiano R, 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.

    PubMed  Google Scholar 

  69. 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: 273–80.

    CAS  Google Scholar 

  70. Wang X, Zhu J, Chen J, Shang Y. Effects of nicotine on the number and activity of circulating endothelial progenitor cells. J Clin Pharmacol 2004, 44: 881–9.

    PubMed  CAS  Google Scholar 

  71. Kondo T, Hayashi M, Takeshita K, et al. Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. Arterioscler Thromb Vasc Biol 2004, 24: 1442–7.

    PubMed  CAS  Google Scholar 

  72. Scheubel RJ, Zorn H, Silber RE, et al. Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 2003, 42: 2073–80.

    PubMed  Google Scholar 

  73. Heeschen C, Lehmann R, Honold J, et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 2004, 109: 1615–22.

    PubMed  Google Scholar 

  74. Foresta C, Caretta N, Lana A, Cabrelle A, Palù G, Ferlin A. Circulating endothelial progenitor cells in subjects with erectile dysfunction. Int J Impot Res 2005, 17: 288–90.

    PubMed  CAS  Google Scholar 

  75. George J, Herz I, Goldstein E. Number and adhesive properties of circulating endothelial progenitor cells in patients with in-stent restenosis. Arterioscler Thromb Vasc Biol 2003, 23: e57–60.

    PubMed  Google Scholar 

  76. Simper D, Wang S, Deb A, et al. Endothelial progenitor cells are decreased in blood of cardiac allograft patients with vasculopathy and endothelial cells of non cardiac origin are enriched in transplant atherosclerosis. Circulation 2003, 107: 143–9.

    Google Scholar 

  77. George J, Goldstein E, Abashidze S, et al. Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation. Eur Heart J 2004, 25: 1003–8.

    PubMed  CAS  Google Scholar 

  78. Shintani S, Murohara T, Ikeda H, et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001, 103: 2776–9.

    PubMed  CAS  Google Scholar 

  79. Valgimigli M, Rigolin GM, Fucili A, et al. CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation 2004, 110: 1209–12.

    PubMed  CAS  Google Scholar 

  80. Verma S, Kuliszewski MA, Li SH, et al. C-Reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 2004, 109: 2058–67.

    PubMed  CAS  Google Scholar 

  81. Ghani U, Shuaib A, Salam A, et al. Endothelial progenitor cells during cerebrovascular disease. Stroke 2005, 36: 151–3.

    PubMed  Google Scholar 

  82. Waltenberger J. Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications. Cardiovasc Res 2001, 49: 554–60.

    PubMed  CAS  Google Scholar 

  83. Abaci A, Ouzhan A, Kahraman S, et al. Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 1999, 99: 2239–42.

    PubMed  CAS  Google Scholar 

  84. Hibbert B, Olsen S, O’Brien E. Involvement of progenitor cells in vascular repair. Trends Cardiovasc Med 2003, 13: 322–6.

    PubMed  CAS  Google Scholar 

  85. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991, 40: 405–12.

    PubMed  CAS  Google Scholar 

  86. Rosso A, Balsamo A, Gambino R, et al. p53 Mediates the accelerated onset of senescence of endothelial progenitor cells in diabetes. J Biol Chem 2006, 281: 4339–47.

    PubMed  CAS  Google Scholar 

  87. Schatteman GC, Hanlon HD, Jiao C, Dodds SG, Christy BA. Blood-derived angioblasts accelerate blood flow restoration in diabetic mice. J Clin Invest 2000, 106: 571–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  88. Rivard A, Berthou-Soulie L, Principe N, et al. Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J Biol Chem 2000, 275: 29643–7.

    PubMed  CAS  Google Scholar 

  89. Tschudi MR, Barton M, Bersinger NA, et al. Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery. J Clin Invest 1996, 98: 899–905.

    PubMed Central  PubMed  CAS  Google Scholar 

  90. Chang EI, Loh S, Ceradini DJ, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation 2007, 116: 2818–29.

    PubMed  CAS  Google Scholar 

  91. Kunz GA, Liang G, Cuculi F, et al. Circulating endothelial progenitor cells predictcoronary artery disease severity. Am Heart J 2006, 152: 190–5.

    PubMed  Google Scholar 

  92. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005, 353: 999–1007.

    PubMed  CAS  Google Scholar 

  93. Xiao Q, Kiechl S, Patel S, et al. Endothelial progenitor cells, cardiovascular risk factors, cytokine levels and atherosclerosis — results from a large population-based study. PLoS ONE 2007, 2: e975.

    PubMed Central  PubMed  Google Scholar 

  94. Taddei S, Salvetti A. Endothelial dysfunction in essential hypertension: clinical implications. J Hypertens 2002, 20: 1671–4.

    PubMed  CAS  Google Scholar 

  95. Alexander CM, Landsman PB, Teutsch SM, Haffner SM; Third National Health and Nutrition Examination Survey (NHANES III); National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003, 52: 1210–4.

    PubMed  CAS  Google Scholar 

  96. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 2002, 346: 913–23.

    PubMed  CAS  Google Scholar 

  97. Noon JP, Walker BR, Webb DJ, et al. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 1997, 99: 1873–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  98. Antonios TF, Rattray FM, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Rarefaction of skin capillaries in normotensive offspring of individuals with essential hypertension. Heart 2003, 89: 175–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  99. Antonios TF, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Rarefaction of skin capillaries in borderline essential hypertension suggests an early structural abnormality. Hypertension 1999, 34: 655–8.

    PubMed  CAS  Google Scholar 

  100. Le Noble FA, Stassen FR, Hacking WJ, Struijker Boudier HA. Angiogenesis and hypertension. J Hypertens 1998, 16: 1563–72.

    PubMed  Google Scholar 

  101. Vogt CJ, Schmid-Schönbein GW. Microvascular endothelial cell death and rarefaction in the glucocorticoid-induced hypertensive rat. Microcirculation 2001, 8: 129–39.

    PubMed  CAS  Google Scholar 

  102. Gobe G, Browning J, Howard T, et al. Apoptosis occurs in endothelial cells during hypertension-induced microvascular rarefaction. J Struct Biol 1997, 118: 63–72.

    PubMed  CAS  Google Scholar 

  103. Imanishi T, Moriwaki C, Hano T, Nishio I. Endothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertension. J Hypertens 2005, 23: 1831–7.

    PubMed  CAS  Google Scholar 

  104. Delva P, Degan M, Vallerio P, et al. Endothelial progenitor cells in patients with essential hypertension. J Hypertens 2007, 25: 127–32.

    PubMed  CAS  Google Scholar 

  105. Verhovez A, Zeoli A, Williams TA, et al. Primary aldosteronism and endothelial progenitor cell bioavailability. Clin Endocrinol (Oxf) 2008, 69: 528–34.

    CAS  Google Scholar 

  106. Oliveras A, Soler MJ, Martínez-Estrada OM, et al. Endothelial progenitor cells are reduced in refractory hypertension. J Hum Hypertens 2008, 22: 183–90.

    PubMed  CAS  Google Scholar 

  107. Tanito M, Nakamura H, Kwon YW, et al. Enhanced oxidative stress and impaired thioredoxin expression in spontaneously hypertensive rats. Antioxid Redox Signal 2004, 6: 89–97.

    PubMed  CAS  Google Scholar 

  108. Rodriguez-Iturbe B, Zhan CD, Quiroz Y, Sindhu RK, Vaziri ND. Antioxidant-rich diet relieves hypertension and reduces renal immune infiltration in spontaneously hypertensive rats. Hypertension 2003, 41: 341–6.

    PubMed  CAS  Google Scholar 

  109. Nishiyama A, Yao L, Nagai Y, et al. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension 2004, 43: 841–8.

    PubMed  CAS  Google Scholar 

  110. Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 2002, 346: 1954–62.

    PubMed  CAS  Google Scholar 

  111. Lip GY, Edmunds E, Nuttall SL, Landray MJ, Blann AD, Beevers DG. Oxidative stress in malignant and non-malignant phase hypertension. J Hum Hypertens 2002, 16: 333–6.

    PubMed  CAS  Google Scholar 

  112. Harrison DG, Cai H, Landmesser U, Griendling KK. Interactions of angiotensin II with NADPH oxidase, oxidant stress and cardiovascular disease. J Renin Angiotensin Aldosterone Syst 2003, 4: 51–61.

    PubMed  CAS  Google Scholar 

  113. Hakim AA, Petrovitch H, Burchfiel CM, et al. Effects of walking on mortality among nonsmoking retired men. N Engl J Med 1998, 338: 94–9.

    PubMed  CAS  Google Scholar 

  114. Manson JE, Greenland P, LaCroix AZ, et al. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N Engl J Med 2002, 347: 716–25.

    PubMed  Google Scholar 

  115. Belardinelli R, Paolini I, Cianci G, Piva R, Georgiou D, Purcaro A. Exercise training intervention after coronary angioplasty: the ETICA trial. J Am Coll Cardiol 2001, 37: 1891–900.

    PubMed  CAS  Google Scholar 

  116. Hambrecht R, Gielen S, Linke A, et al. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: A randomized trial. JAMA 2000, 283: 3095–101.

    PubMed  CAS  Google Scholar 

  117. Hambrecht R, Fiehn E, Weigl C, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 1998, 98: 2709–15.

    PubMed  CAS  Google Scholar 

  118. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996, 93: 210–4.

    PubMed  CAS  Google Scholar 

  119. Laufs U, Werner N., Link A., et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 2004, 109: 220–6.

    PubMed  CAS  Google Scholar 

  120. 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.

    PubMed  CAS  Google Scholar 

  121. Rupp S, Bardoff C, Koyanagi M, et al. Statin therapy in patients with coronary artery disease improves the impaired endothelial progenitor cell differentiation into cardiomyogenic cells. Basic Res Cardiol 2004, 99: 61–8.

    PubMed  CAS  Google Scholar 

  122. Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005, 111: 2356–63.

    PubMed  CAS  Google Scholar 

  123. Bahlmann FH, DeGroot K, Duckert T, et al. Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int 2003, 64: 1648–52.

    PubMed  CAS  Google Scholar 

  124. Strehlow K, Werner N, Berweiler J, et al. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation 2003, 107: 3059–65.

    PubMed  CAS  Google Scholar 

  125. Devin JK, Young PP. The effects of growth hormone and insulin-like growth factor-1 on the aging cardiovascular system and its progenitor cells. Curr Opin Investig Drugs 2008, 9: 983–92.

    PubMed  CAS  Google Scholar 

  126. Thum T Hoeber S, Froese S, et al. Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1. Circ Res 2007, 100: 434–43.

    PubMed  CAS  Google Scholar 

  127. Pistrosch F, Herbrig K, Oelschlaegel U, et al. PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis 2005, 183: 163–7.

    PubMed  CAS  Google Scholar 

  128. Min TQ, Zhu CJ, Xiang WX, Hui ZJ, Peng SY. Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease. Cardiovasc Drugs Ther 2004, 18: 203–9.

    PubMed  CAS  Google Scholar 

  129. Bahlmann FH, Groot KD, 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: 526–9.

    CAS  Google Scholar 

  130. Kureishi Y, Lou Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000, 6: 1004–10.

    PubMed Central  PubMed  CAS  Google Scholar 

  131. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001, 108: 399–405.

    PubMed Central  PubMed  CAS  Google Scholar 

  132. Landmesser U, Engberding N, Bahlmann FH, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 2004, 110: 1933–9.

    PubMed  CAS  Google Scholar 

  133. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998, 273: 24266–71.

    PubMed  CAS  Google Scholar 

  134. Fulton D, Gratton JP, McCabe TJ, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999, 199: 597–601.

    Google Scholar 

  135. Dimmeler S, Aicher A, Vasa M, et al. HMG-CoAreductase inhibitors statins increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001, 108: 391–7.

    PubMed Central  PubMed  CAS  Google Scholar 

  136. Walter DH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization A novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002, 105: 3017–24.

    PubMed  CAS  Google Scholar 

  137. Spyridopoulos, Haendeler J, Urbich C, et al. Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation 2004, 110: 3136–42.

    PubMed  CAS  Google Scholar 

  138. Assmus B, Urbich C, Aicher A, et al. HMG-CoAreductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res 2003, 92: 1049–55.

    PubMed  CAS  Google Scholar 

  139. Iwakura A, Luedemann C, Shastry S, et al. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 2003, 108: 3115–21.

    PubMed  CAS  Google Scholar 

  140. Fadini GP, de Kreutzenberg S, Albiero M, et al. Gender differences in endothelial progenitor cells and cardiovascular risk profile: the role of female estrogens. Arterioscler Thromb Vasc Biol 2008, 28: 997–1004.

    PubMed  CAS  Google Scholar 

  141. Wang CH, Ciliberti N, Li SH, et al. Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: a new paradigm in glitazone pleiotropy. Circulation 2004, 109: 1392–400.

    PubMed  Google Scholar 

  142. Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 2003, 23: 52–7.

    PubMed  CAS  Google Scholar 

  143. Wang CH, Ting MK, Verma S, et al. Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus. Am Heart J 2006, 152: 1051.e1–8.

    Google Scholar 

  144. Yao EH, Fukuda N, Matsumoto T, et al. Losartan improves the impaired function of endothelial progenitor cells in hypertension via an antioxidant effect. Hypertens Res 2007, 30: 1119–28.

    PubMed  Google Scholar 

  145. Kawamoto A, Gwon H-C, Iwaguro H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001, 103: 634–7.

    PubMed  CAS  Google Scholar 

  146. Kaushal S, Amiel GE, Guleserian KJ, et al. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat Med 2001, 7: 1035–40.

    PubMed Central  PubMed  CAS  Google Scholar 

  147. Kawamoto A, Tkebuchava T, Yamaguchi J-I, et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization. Circulation 2003, 107: 461–8.

    PubMed  Google Scholar 

  148. Kubota Y, Kishi K, Satoh H, et al. Transplanted endothelial progenitor cells augment the survival areas of rat dorsal flaps. Cell Transplant 2003, 12: 647–57.

    PubMed  Google Scholar 

  149. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature 2001, 410: 701–5.

    PubMed  CAS  Google Scholar 

  150. Shirota T, Yasui H, Shimokawa H, Matsuda T. Fabrication of endothelial progenitor cell EPC-seeded intravascular stent devices and in vitro endothelialization on hybrid vascular tissue. Biomaterials 2003, 24: 2295–302.

    PubMed  CAS  Google Scholar 

  151. Gulati R, Jevremovic D, Peterson TE, et al. Autologous culture-modified mononuclear cells confer vascular protection after arterial injury. Circulation 2003, 108: 1520–6.

    PubMed  Google Scholar 

  152. He T, Smith LA, Harrington S, Nath KA, Caplice NM, Katusic ZS. Transplantation of circulating endothelial progenitor cells restores endothelial function of denuded rabbit arteries. Stroke 2004, 35: 2378–84.

    PubMed  Google Scholar 

  153. Nowak G, Karrar A, Holmén C, et al. Expression of vascular endothelial factor receptor-2 or Tie-2 on peripheral blood cells defines functionally competent cell populations capable of reendothelialization. Circulation 2004, 110: 3699–707.

    PubMed  CAS  Google Scholar 

  154. Matsumura G, Miyagawa-Tomita S, Shin’oka T, Ikada Y, Kurosawa H. First evidence that bone marrow cells contribute to the construction of tissue-engineered vascular autografts in vivo. Circulation 2003, 108: 1729–34.

    PubMed  Google Scholar 

  155. Aoki J, Serruys PW, van Beusekom H, et al. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol 2005, 45: 1574–9.

    PubMed  CAS  Google Scholar 

  156. Rotmans JI, Heyligers JM, Verhagen HJ, et al. In vivo cell seeding with anti-CD34 antibodies successfully accelerates endothelialization but stimulates intimal hyperplasia in porcine arteriovenous expanded polytetrafluoroethylene grafts. Circulation 2005, 112: 12–8.

    PubMed  CAS  Google Scholar 

  157. Stamm C, Westphal B, Kleine H-D, et al. Autologous bone-marrow transplantation for myocardial regeneration. Lancet 2003, 361: 45–6.

    PubMed  Google Scholar 

  158. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002, 106: 1913–8.

    PubMed  Google Scholar 

  159. Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in acute Myocardial Infarction TOPCARE-AMI. Circulation 2002, 106: 3009–17.

    PubMed  Google Scholar 

  160. Wollert KC, Meyer GP, Latz J, et al. Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST randomized controlled clinical trial. Lancet 2004, 364: 141–8.

    PubMed  Google Scholar 

  161. Fernández-Avilés F, San Roman JA, García-Frade J, et al. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res 2004, 95: 742–8.

    PubMed  Google Scholar 

  162. Hamano K, Nishida M, Hirata K, et al. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results. Jpn Circ J 2001, 65: 845–7.

    PubMed  CAS  Google Scholar 

  163. Tse HF, Kwong YL, Chan JKF, Lo G, Ho CL, Lau CP. Angiogenesis in ischemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003, 361: 47–9.

    PubMed  Google Scholar 

  164. Perin EC, Dohmann HFR, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003, 107: 2294–302.

    PubMed  Google Scholar 

  165. Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic angiogenesis for patients with limb ischemia by autologous transplantation of bone marrow cells: a pilotstudy and a randomised controlled trial. Lancet 2002, 360: 427–35.

    Google Scholar 

  166. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006, 367: 113–21.

    PubMed  Google Scholar 

  167. Schächinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial. J Am Coll Cardiol 2004, 44: 1690–9.

    PubMed  Google Scholar 

  168. Assmus B, Honold J, Schächinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006, 355: 1222–32.

    PubMed  CAS  Google Scholar 

  169. Schächinger V, Erbs S, Elsässer A, et al; REPAIR-AMI Investigators. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006, 355: 1210–21.

    PubMed  Google Scholar 

  170. Lunde K, Solheim S, Aakhus S,et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006, 355: 1199–209.

    PubMed  CAS  Google Scholar 

  171. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: Double-blind, randomised controlled trial. Lancet 2006, 367: 113–21.

    PubMed  Google Scholar 

  172. Yoon YS, Park JS, Tkebuchava T, Luedeman C, Losordo DW. Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction. Circulation 2004, 109: 3154–7.

    PubMed  Google Scholar 

  173. Caplice NM, Bunch TJ, Stalboerger PG, et al. Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci U S A 2003, 100: 4754–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  174. Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002, 8: 403–9.

    PubMed  CAS  Google Scholar 

  175. Ince H, Petzsch M, Kleine HD, et al. Prevention of left ventricular remodeling with granulocyte colony-stimulating factor after acute myocardial infarction: final 1-year results of the front-integrated revascularization and Stem Cell Liberation In Evolving Acute Myocardial Infarction By Granulocyte Colony-Stimulating Factor (FIRSTLINE-AMI) trial. Circulation 2005, 112: 173–80.

    Google Scholar 

  176. Nienaber CA, Petzsch M, Kleine HD, Eckard H, Freund M, Ince H. Effects of granulocyte-colony-stimulating factor on mobilization of bone-marrow-derived stem cells after myocardial infarction in humans. Nat Clin Pract Cardiovasc Med 2006, 3(Suppl 1): S73–7.

    PubMed  CAS  Google Scholar 

  177. Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006: 1003–10.

  178. Zohlnhofer D, Kastrati A, Schomig A. Stem cell mobilization by granulocyte-colony-stimulating factor in acute myocardial infarction: lessons from the REVIVAL-2 trial. Nat Clin Pract Cardiovasc Med 2007, 4: S106–9.

    PubMed  Google Scholar 

  179. Ellis SG, Penn MS, Bolwell B, et al. Granulocyte colony stimulating factor in patients with large acute myocardial infarction: results of a pilot dose-escalation randomized trial. Am Heart J 2006, 152: e9–14.

    PubMed  Google Scholar 

  180. Ripa RS, Jorgensen E, Wang Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: Result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 2006, 113: 1983–92.

    PubMed  CAS  Google Scholar 

  181. Azarnoush K, Maurel A, Sebbah L, et al. Enhancement of the functional benefits of skeletal myoblast transplantation by means of coadministration of hypoxia-inducible factor 1alpha. J Thorac Cardiovasc Surg 2005, 130: 173–9.

    PubMed  CAS  Google Scholar 

  182. Niagara MI, Haider H, Jiang S, Ashraf M. Pharmacologically preconditioned skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis via release of paracrine factors in the infarcted heart. Circ Res 2007, 100: 545–55.

    PubMed  CAS  Google Scholar 

  183. Murasawa S, Llevadot J, Silver M, Isner JM, Losordo DW, Asahara T. Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells. Circulation 2002, 106: 1133–9.

    PubMed  CAS  Google Scholar 

  184. Seeger FH, Zeiher A, Dimmeler S. Cell-enhancement strategies for the treatment of ischemic heart disease. Nat Clin Prac Cardiovascular Med 2006, 4: S110–3.

    Google Scholar 

  185. De Palma M, Naldini L. Role of haematopoietic cells and endothelial progenitors in tumour angiogenesis. Biochim Biophys Acta 2006, 1766: 159–66.

    PubMed  Google Scholar 

  186. Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 2006, 313: 1785–7.

    PubMed  CAS  Google Scholar 

  187. Ferrari N, Glod J, Lee J, Kobiler D, Fine HA. Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective genetargeting vectors. Gene Ther 2003, 10: 647–56.

    PubMed  CAS  Google Scholar 

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  1. Department of Internal Medicine, University of Torino, Corso Dogliotti 14, 10126, Torino, Italy

    A. Zeoli, P. Dentelli & M. F. Brizzi MD

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Zeoli, A., Dentelli, P. & Brizzi, M.F. Endothelial progenitor cells and their potential clinical implication in cardiovascular disorders. J Endocrinol Invest 32, 370–382 (2009). https://doi.org/10.1007/BF03345729

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