Therapy for the Coronary Circulation

  • Robert J. Tomanek


The need to maintain or enhance myocardial perfusion is apparent from the many conditions in which coronary vascular reserve is limited or flow is impeded to the extent that ischemia and death can occur. Examples, as described in the preceding chapters of this book, include coronary anomalies, changes associated with aging, coronary artery disease, cardiac hypertrophy, and coronary vascular dysfunction. The classical treatments are pharmacological or mechanical revascularization therapies. Pharmacological approaches are aimed at reducing O2 demand, increasing its utilization, or enhancing myocardial perfusion by improving vascular reactivity. Surgical or percutaneous mechanical interventions are used to correct coronary anomalies, open occluded channels, or provide vascular bypass for severely occluded arteries. More recently gene and cell therapy have been proposed as ways of increasing vascular capacity to prevent ischemic events. These approaches have great potential. The goal of this chapter is to summarize the effects of pharmacological, gene, protein, and stem cell therapies on myocardial perfusion.


Vascular Endothelial Growth Factor Myocardial Perfusion Infarct Size Capillary Density Intramyocardial Injection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Endothelial cell


Endothelial progenitor cell


Fibroblast growth factor


Granulocyte-colony stimulating factor


Hypoxia inducible factor


Monocyte chemoattractant-1


Mesenchymal stem cell


Stromal-derived factor


Vascular endothelial growth factor


Vascular smooth muscle cell


  1. 1.
    Gupta R, Tongers J, Losordo DW. Human studies of angiogenic gene therapy. Circ Res. 2009;105:724–36.PubMedGoogle Scholar
  2. 2.
    Kastrup J. Gene therapy and angiogenesis in patients with coronary artery disease. Exp Rev Cardiovasc Ther. 2010;8:1127–38.Google Scholar
  3. 3.
    Lavu M, Gundewar S, Lefer DJ. Gene therapy for ischemic heart disease. J Mol Cell Cardiol. 2011;50:742–50.PubMedGoogle Scholar
  4. 4.
    Eibel B, Rodrigues CG, Giusti II, Nesralla IA, Prates PR, Sant’Anna RT, et al. Gene therapy for ischemic heart disease: review of clinical trials. Rev Bras Cir Cardiovasc. 2011;26:635–46.PubMedGoogle Scholar
  5. 5.
    Hedman M, Hartikainen J, Syvanne M, Stjernvall J, Hedman A, Kivela A, et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation. 2003;107:2677–83.PubMedGoogle Scholar
  6. 6.
    Kastrup J, Jorgensen E, Ruck A, Tagil K, Glogar D, Ruzyllo W, et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol. 2005;45:982–8.PubMedGoogle Scholar
  7. 7.
    Gyongyosi M, Khorsand A, Zamini S, Sperker W, Strehblow C, Kastrup J, et al. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation. 2005;112:I157–65.PubMedGoogle Scholar
  8. 8.
    Stewart DJ, Kutryk MJ, Fitchett D, Freeman M, Camack N, Su Y, et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther. 2009;17:1109–15.PubMedGoogle Scholar
  9. 9.
    Tio RA, Tan ES, Jessurun GA, Veeger N, Jager PL, Slart RH, et al. PET for evaluation of differential myocardial perfusion dynamics after VEGF gene therapy and laser therapy in end-stage coronary artery disease. J Nucl Med. 2004;45:1437–43.PubMedGoogle Scholar
  10. 10.
    Symes JF, Losordo DW, Vale PR, Lathi KG, Esakof DD, Mayskiy M, et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg. 1999;68:830–6. discussion 6–7.PubMedGoogle Scholar
  11. 11.
    Sylven C, Sarkar N, Ruck A, Drvota V, Hassan SY, Lind B, et al. Myocardial Doppler tissue velocity improves following myocardial gene therapy with VEGF-A165 plasmid in patients with inoperable angina pectoris. Coron Artery Dis. 2001;12:239–43.PubMedGoogle Scholar
  12. 12.
    Ripa RS, Wang Y, Jorgensen E, Johnsen HE, Hesse B, Kastrup J. Intramyocardial injection of vascular endothelial growth factor-A165 plasmid followed by granulocyte-colony stimulating factor to induce angiogenesis in patients with severe chronic ischaemic heart disease. Eur Heart J. 2006;27:1785–92.PubMedGoogle Scholar
  13. 13.
    Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation. 2003;107:1359–65.PubMedGoogle Scholar
  14. 14.
    Stewart DJ, Hilton JD, Arnold JM, Gregoire J, Rivard A, Archer SL, et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther. 2006;13:1503–11.PubMedGoogle Scholar
  15. 15.
    Kastrup J, Jorgensen E, Fuchs S, Nikol S, Botker HE, Gyongyosi M, et al. A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial. EuroIntervention. 2011;6:813–8.PubMedGoogle Scholar
  16. 16.
    Losordo DW, Vale PR, Hendel RC, Milliken CE, Fortuin FD, Cummings N, et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation. 2002;105:2012–8.PubMedGoogle Scholar
  17. 17.
    Fortuin FD, Vale P, Losordo DW, Symes J, DeLaria GA, Tyner JJ, et al. One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients. Am J Cardiol. 2003;92:436–9.PubMedGoogle Scholar
  18. 18.
    Reilly JP, Grise MA, Fortuin FD, Vale PR, Schaer GL, Lopez J, et al. Long-term (2-year) clinical events following transthoracic intramyocardial gene transfer of VEGF-2 in no-option patients. J Interv Cardiol. 2005;18:27–31.PubMedGoogle Scholar
  19. 19.
    Schumacher B, Stegmann T, Pecher P. The stimulation of neoangiogenesis in the ischemic human heart by the growth factor FGF: first clinical results. J Cardiovasc Surg (Torino). 1998;39:783–9.Google Scholar
  20. 20.
    Sellke FW, Laham RJ, Edelman ER, Pearlman JD, Simons M. Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results. Ann Thorac Surg. 1998;65:1540–4.PubMedGoogle Scholar
  21. 21.
    Laham RJ, Sellke FW, Edelman ER, Pearlman JD, Ware JA, Brown DL, et al. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial. Circulation. 1999;100:1865–71.PubMedGoogle Scholar
  22. 22.
    Laham RJ, Chronos NA, Pike M, Leimbach ME, Udelson JE, Pearlman JD, et al. Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study. J Am Coll Cardiol. 2000;36:2132–9.PubMedGoogle Scholar
  23. 23.
    Simons M, Annex BH, Laham RJ, Kleiman N, Henry T, Dauerman H, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation. 2002;105:788–93.PubMedGoogle Scholar
  24. 24.
    Henry TD, Grines CL, Watkins MW, Dib N, Barbeau G, Moreadith R, et al. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol. 2007;50:1038–46.PubMedGoogle Scholar
  25. 25.
    Grines CL, Watkins MW, Mahmarian JJ, Iskandrian AE, Rade JJ, Marrott P, et al. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J Am Coll Cardiol. 2003;42:1339–47.PubMedGoogle Scholar
  26. 26.
    Banai S, Jaklitsch MT, Casscells W, Shou M, Shrivastav S, Correa R, et al. Effects of acidic fibroblast growth factor on normal and ischemic myocardium. Circ Res. 1991;69:76–85.PubMedGoogle Scholar
  27. 27.
    Unger EF, Banai S, Shou M, Lazarous DF, Jaklitsch MT, Scheinowitz M, et al. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model. Am J Physiol. 1994;266:H1588–95.PubMedGoogle Scholar
  28. 28.
    Lazarous DF, Shou M, Scheinowitz M, Hodge E, Thirumurti V, Kitsiou AN, et al. Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation. 1996;94:1074–82.PubMedGoogle Scholar
  29. 29.
    Unger EF, Banai S, Shou M, Jaklitsch M, Hodge E, Correa R, et al. A model to assess interventions to improve collateral blood flow: continuous administration of agents into the left coronary artery in dogs. Cardiovasc Res. 1993;27:785–91.PubMedGoogle Scholar
  30. 30.
    Harada K, Grossman W, Friedman M, Edelman ER, Prasad PV, Keighley CS, et al. Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts. J Clin Invest. 1994;94:623–30.PubMedGoogle Scholar
  31. 31.
    Liu Y, Sun L, Huan Y, Zhao H, Deng J. Effects of basic fibroblast growth factor microspheres on angiogenesis in ischemic myocardium and cardiac function: analysis with dobutamine cardiovascular magnetic resonance tagging. Eur J Cardiothorac Surg. 2006;30:103–7.PubMedGoogle Scholar
  32. 32.
    Giordano FJ, Ping P, McKirnan MD, Nozaki S, DeMaria AN, Dillmann WH, et al. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med. 1996;2:534–9.PubMedGoogle Scholar
  33. 33.
    Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, et al. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation. 1994;89:2183–9.PubMedGoogle Scholar
  34. 34.
    Pearlman JD, Hibberd MG, Chuang ML, Harada K, Lopez JJ, Gladstone SR, et al. Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis. Nat Med. 1995;1:1085–9.PubMedGoogle Scholar
  35. 35.
    Lazarous DF, Shou M, Stiber JA, Hodge E, Thirumurti V, Goncalves L, et al. Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis. Cardiovasc Res. 1999;44:294–302.PubMedGoogle Scholar
  36. 36.
    Besse S, Boucher F, Linguet G, Riou L, De Leiris J, Riou B, et al. Intramyocardial protein therapy with vascular endothelial growth factor (VEGF-165) induces functional angiogenesis in rat senescent myocardium. J Physiol Pharmacol. 2010;61:651–61.PubMedGoogle Scholar
  37. 37.
    Shyu KG, Wang MT, Wang BW, Chang CC, Leu JG, Kuan P, et al. Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res. 2002;54:576–83.PubMedGoogle Scholar
  38. 38.
    Hwang H, Kloner RA. Improving regenerating potential of the heart after myocardial infarction: factor-based approach. Life Sci. 2010;86:461–72.PubMedGoogle Scholar
  39. 39.
    Edelberg JM, Lee SH, Kaur M, Tang L, Feirt NM, McCabe S, et al. Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heart. Circulation. 2002;105:608–13.PubMedGoogle Scholar
  40. 40.
    Zhao T, Zhang D, Millard RW, Ashraf M, Wang Y. Stem cell homing and angiomyogenesis in transplanted hearts are enhanced by combined intramyocardial SDF-1alpha delivery and endogenous cytokine signaling. Am J Physiol Heart Circ Physiol. 2009;296:H976–86.PubMedGoogle Scholar
  41. 41.
    Zaruba MM, Huber BC, Brunner S, Deindl E, David R, Fischer R, et al. Parathyroid hormone treatment after myocardial infarction promotes cardiac repair by enhanced neovascularization and cell survival. Cardiovasc Res. 2008;77:722–31.PubMedGoogle Scholar
  42. 42.
    Schatteman GC, Awad O. Hemangioblasts, angioblasts, and adult endothelial cell progenitors. Anat Rec A Discov Mol Cell Evol Biol. 2004;276:13–21.PubMedGoogle Scholar
  43. 43.
    Ribatti D. The discovery of endothelial progenitor cells. An historical review. Leuk Res. 2007;31:439–44.PubMedGoogle Scholar
  44. 44.
    Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999;18:3964–72.PubMedGoogle Scholar
  45. 45.
    Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, et al. Evidence for circulating bone marrow-derived endothelial cells. Blood. 1998;92:362–7.PubMedGoogle Scholar
  46. 46.
    Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res. 2012;110:624–37.PubMedGoogle Scholar
  47. 47.
    Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M, et al. In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood. 2000;95:3106–12.PubMedGoogle Scholar
  48. 48.
    Yamahara K, Itoh H. Potential use of endothelial progenitor cells for regeneration of the vasculature. Ther Adv Cardiovasc Dis. 2009;3:17–27.PubMedGoogle Scholar
  49. 49.
    Masuda H, Alev C, Akimaru H, Ito R, Shizuno T, Kobori M, et al. Methodological development of a clonogenic assay to determine endothelial progenitor cell potential. Circ Res. 2011;109:20–37.PubMedGoogle Scholar
  50. 50.
    Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, 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.PubMedGoogle Scholar
  51. 51.
    Kawamoto A, Iwasaki H, Kusano K, Murayama T, Oyamada A, Silver M, et al. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation. 2006;114:2163–9.PubMedGoogle Scholar
  52. 52.
    Ramos AL, Darabi R, Akbarloo N, Borges L, Catanese J, Dineen SP, et al. Clonal analysis reveals a common progenitor for endothelial, myeloid, and lymphoid precursors in umbilical cord blood. Circ Res. 2010;107:1460–9.PubMedGoogle Scholar
  53. 53.
    Padfield GJ, Newby DE, Mills NL. Understanding the role of endothelial progenitor cells in percutaneous coronary intervention. J Am Coll Cardiol. 2010;55:1553–65.PubMedGoogle Scholar
  54. 54.
    Madeddu P, Emanueli C, Pelosi E, Salis MB, Cerio AM, Bonanno G, et al. Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. FASEB J. 2004;18:1737–9.PubMedGoogle Scholar
  55. 55.
    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:e20–5.PubMedGoogle Scholar
  56. 56.
    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.PubMedGoogle Scholar
  57. 57.
    Weber G, Losi M, Toti P, Vatti R. Circulating endothelial-like cells in arterial peripheral blood of hypercholesterolemic rabbits. Artery. 1979;5:29–36.PubMedGoogle Scholar
  58. 58.
    Mund JA, Estes ML, Yoder MC, Ingram Jr DA, Case J. Flow cytometric identification and functional characterization of immature and mature circulating endothelial cells. Arterioscler Thromb Vasc Biol. 2012;32:1045–53.PubMedGoogle Scholar
  59. 59.
    Richardson MR, Yoder MC. Endothelial progenitor cells: quo vadis? J Mol Cell Cardiol. 2011;50:266–72.PubMedGoogle Scholar
  60. 60.
    Yoder MC. Is endothelium the origin of endothelial progenitor cells? Arterioscler Thromb Vasc Biol. 2010;30:1094–103.PubMedGoogle Scholar
  61. 61.
    Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol. 2008;28:1584–95.PubMedGoogle Scholar
  62. 62.
    Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95:343–53.PubMedGoogle Scholar
  63. 63.
    Romagnani P, Annunziato F, Liotta F, Lazzeri E, Mazzinghi B, Frosali 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.PubMedGoogle Scholar
  64. 64.
    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.PubMedGoogle Scholar
  65. 65.
    Bautch VL. Stem cells and the vasculature. Nat Med. 2011;17:1437–43.PubMedGoogle Scholar
  66. 66.
    Torsney E, Xu Q. Resident vascular progenitor cells. J Mol Cell Cardiol. 2011;50:304–11.PubMedGoogle Scholar
  67. 67.
    Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circulation Res. 2004;95:911–21.PubMedGoogle Scholar
  68. 68.
    Barile L, Messina E, Giacomello A, Marban E. Endogenous cardiac stem cells. Prog Cardiovasc Dis. 2007;50:31–48.PubMedGoogle Scholar
  69. 69.
    Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, et al. Human cardiac stem cells. Proc Natl Acad Sci USA. 2007;104:14068–73.PubMedGoogle Scholar
  70. 70.
    Zengin E, Chalajour F, Gehling UM, Ito WD, Treede H, Lauke H, et al. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development. 2006;133:1543–51.PubMedGoogle Scholar
  71. 71.
    Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004;364:141–8.PubMedGoogle Scholar
  72. 72.
    Bartunek J, Vanderheyden M, Vandekerckhove B, Mansour S, De Bruyne B, De Bondt P, et al. Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety. Circulation. 2005;112:I178–83.PubMedGoogle Scholar
  73. 73.
    Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106:1913–8.PubMedGoogle Scholar
  74. 74.
    Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, 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.PubMedGoogle Scholar
  75. 75.
    Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, 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.PubMedGoogle Scholar
  76. 76.
    Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355:1199–209.PubMedGoogle Scholar
  77. 77.
    Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106:3009–17.PubMedGoogle Scholar
  78. 78.
    Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92–5.PubMedGoogle Scholar
  79. 79.
    Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25:2739–49.PubMedGoogle Scholar
  80. 80.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell stem cell. 2008;3:301–13.PubMedGoogle Scholar
  81. 81.
    Gojo S, Gojo N, Takeda Y, Mori T, Abe H, Kyo S, et al. In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells. Exp Cell Res. 2003;288:51–9.PubMedGoogle Scholar
  82. 82.
    Segers VF, Van Riet I, Andries LJ, Lemmens K, Demolder MJ, De Becker AJ, et al. Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms. Am J Physiol Heart Circ Physiol. 2006;290:H1370–7.PubMedGoogle Scholar
  83. 83.
    Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002;53:31–47.PubMedGoogle Scholar
  84. 84.
    Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005;112:1128–35.PubMedGoogle Scholar
  85. 85.
    Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci USA. 2003;100:2426–31.PubMedGoogle Scholar
  86. 86.
    Dresske B, El Mokhtari NE, Ungefroren H, Ruhnke M, Plate V, Janssen D, et al. Multipotent cells of monocytic origin improve damaged heart function. Am J Transplant. 2006;6:947–58.PubMedGoogle Scholar
  87. 87.
    Fujiyama S, Amano K, Uehira K, Yoshida M, Nishiwaki Y, Nozawa Y, 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.PubMedGoogle Scholar
  88. 88.
    Bruno S, Bussolati B, Scacciatella P, Marra S, Sanavio F, Tarella C, et al. Combined administration of G-CSF and GM-CSF stimulates monocyte-derived pro-angiogenic cells in patients with acute myocardial infarction. Cytokine. 2006;34:56–65.PubMedGoogle Scholar
  89. 89.
    Leor J, Rozen L, Zuloff-Shani A, Feinberg MS, Amsalem Y, Barbash IM, et al. Ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart. Circulation. 2006;114:I94–100.PubMedGoogle Scholar
  90. 90.
    van Royen N, Piek JJ, Schaper W, Fulton WF. A critical review of clinical arteriogenesis research. J Am Coll Cardiol. 2009;55:17–25.PubMedGoogle Scholar
  91. 91.
    Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, et al. Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res. 2000;86:1198–202.PubMedGoogle Scholar
  92. 92.
    Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005;39:733–42.PubMedGoogle Scholar
  93. 93.
    Ziche M, Morbidelli L. Nitric oxide and angiogenesis. J Neurooncol. 2000;50:139–48.PubMedGoogle Scholar
  94. 94.
    Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003;9:1370–6.PubMedGoogle Scholar
  95. 95.
    Strehlow K, Werner N, Berweiler J, Link A, Dirnagl U, Priller J, et al. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation. 2003;107:3059–65.PubMedGoogle Scholar
  96. 96.
    Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5:434–8.PubMedGoogle Scholar
  97. 97.
    Amano K, Okigaki M, Adachi Y, Fujiyama S, Mori Y, Kosaki A, et al. Mechanism for IL-1 beta-mediated neovascularization unmasked by IL-1 beta knock-out mice. J Mol Cell Cardiol. 2004;36:469–80.PubMedGoogle Scholar
  98. 98.
    Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation. 2003;107:1322–8.PubMedGoogle Scholar
  99. 99.
    Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001;103:2885–90.PubMedGoogle Scholar
  100. 100.
    Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, et al. HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells. J Clin Invest. 2001;108:399–405.PubMedGoogle Scholar
  101. 101.
    Walter DH, Rittig K, Bahlmann FH, Kirchmair R, Silver M, Murayama T, 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.PubMedGoogle Scholar
  102. 102.
    Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001;108:391–7.PubMedGoogle Scholar
  103. 103.
    Adams V, Lenk K, Linke A, Lenz D, Erbs S, Sandri M, et al. Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia. Arterioscler Thromb Vasc Biol. 2004;24:684–90.PubMedGoogle Scholar
  104. 104.
    Chih S, Macdonald PS, McCrohon JA, Ma D, Moore J, Feneley MP, et al. Granulocyte colony stimulating factor in chronic angina to stimulate neovascularisation: a placebo controlled crossover trial. Heart. 2012;98:282–90.PubMedGoogle Scholar
  105. 105.
    Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–19.PubMedGoogle Scholar
  106. 106.
    Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell. 2006;124:175–89.PubMedGoogle Scholar
  107. 107.
    Ziegelhoeffer T, Fernandez B, Kostin S, Heil M, Voswinckel R, Helisch A, et al. Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res. 2004;94:230–8.PubMedGoogle Scholar
  108. 108.
    Tillmanns J, Rota M, Hosoda T, Misao Y, Esposito G, Gonzalez A, et al. Formation of large coronary arteries by cardiac progenitor cells. Proc Natl Acad Sci USA. 2008;105:1668–73.PubMedGoogle Scholar
  109. 109.
    Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94:678–85.PubMedGoogle Scholar
  110. 110.
    Schatteman GC, Awad O, Nau E, Wang C, Jiao C, Tomanek RJ, et al. Lin- cells mediate tissue repair by regulating MCP-1/CCL-2. Am J Pathol. 2010;177:2002–10.PubMedGoogle Scholar
  111. 111.
    Wu Y, Ip JE, Huang J, Zhang L, Matsushita K, Liew CC, et al. Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infarcted myocardium. Circ Res. 2006;99:315–22.PubMedGoogle Scholar
  112. 112.
    Aicher A, Brenner W, Zuhayra M, Badorff C, Massoudi S, Assmus B, et al. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation. 2003;107:2134–9.PubMedGoogle Scholar
  113. 113.
    Rehman J, Li J, Parvathaneni L, Karlsson G, Panchal VR, Temm CJ, et al. Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells. J Am Coll Cardiol. 2004;43:2314–8.PubMedGoogle Scholar
  114. 114.
    Penn MS, Ellis S, Gandhi S, Greenbaum A, Hodes Z, Mendelsohn FO, et al. Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: phase I clinical study. Circ Res. 2012;110:304–11.PubMedGoogle Scholar
  115. 115.
    Ratajczak MZ, Shin DM, Liu R, Mierzejewska K, Ratajczak J, Kucia M, et al. Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation—an update and comparison to other primitive small stem cells isolated from adult tissues. Aging. 2012;4(4):235–46.PubMedGoogle Scholar
  116. 116.
    Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20:847–56.PubMedGoogle Scholar
  117. 117.
    Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant. 2011;26:1474–83.PubMedGoogle Scholar
  118. 118.
    Beaudoin AR, Grondin G. Shedding of vesicular material from the cell surface of eukaryotic cells: different cellular phenomena. Biochim Biophys Acta. 1991;1071:203–19.PubMedGoogle Scholar
  119. 119.
    Herrera MB, Fonsato V, Gatti S, Deregibus MC, Sordi A, Cantarella D, et al. Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med. 2010;14:1605–18.PubMedGoogle Scholar
  120. 120.
    Leistner DM, Zeiher AM. Novel avenues for cell therapy in acute myocardial infarction. Circ Res. 2012;110:195–7.PubMedGoogle Scholar
  121. 121.
    Laflamme MA, Zbinden S, Epstein SE, Murry CE. Cell-based therapy for myocardial ischemia and infarction: pathophysiological mechanisms. Annu Rev Pathol. 2007;2:307–39.PubMedGoogle Scholar
  122. 122.
    Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107:2294–302.PubMedGoogle Scholar
  123. 123.
    Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet. 2003;361:47–9.PubMedGoogle Scholar
  124. 124.
    Beeres SL, Bax JJ, Kaandorp TA, Zeppenfeld K, Lamb HJ, Dibbets-Schneider P, et al. Usefulness of intramyocardial injection of autologous bone marrow-derived mononuclear cells in patients with severe angina pectoris and stress-induced myocardial ischemia. Am J Cardiol. 2006;97:1326–31.PubMedGoogle Scholar
  125. 125.
    Hamano K, Nishida M, Hirata K, Mikamo A, Li TS, Harada M, 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.PubMedGoogle Scholar
  126. 126.
    Briguori C, Reimers B, Sarais C, Napodano M, Pascotto P, Azzarello G, et al. Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina. Am Heart J. 2006;151:674–80.PubMedGoogle Scholar
  127. 127.
    Fuchs S, Kornowski R, Weisz G, Satler LF, Smits PC, Okubagzi P, et al. Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease. Am J Cardiol. 2006;97:823–9.PubMedGoogle Scholar
  128. 128.
    Tse HF, Lau CP. Therapeutic angiogenesis with bone marrow–derived stem cells. J Cardiovasc Pharmacol Ther. 2007;12:89–97.PubMedGoogle Scholar
  129. 129.
    Hosoda T. C-kit-positive cardiac stem cells and myocardial regeneration. Am J Cardiovasc Dis. 2012;2:58–67.PubMedGoogle Scholar
  130. 130.
    van Ramshorst J, Bax JJ, Beeres SL, Dibbets-Schneider P, Roes SD, Stokkel MP, et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA. 2009;301:1997–2004.PubMedGoogle Scholar
  131. 131.
    Losordo DW, Henry TD, Davidson C, Sup Lee J, Costa MA, Bass T, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109:428–36.PubMedGoogle Scholar
  132. 132.
    Gowdak LH, Schettert IT, Rochitte CE, Lisboa LA, Dallan LA, Cesar LA, et al. Early increase in myocardial perfusion after stem cell therapy in patients undergoing incomplete coronary artery bypass surgery. J Cardiovasc Transl Res. 2011;4:106–13.PubMedGoogle Scholar
  133. 133.
    Chan CW, Kwong YL, Kwong RY, Lau CP, Tse HF. Improvement of myocardial perfusion reserve detected by cardiovascular magnetic resonance after direct endomyocardial implantation of autologous bone marrow cells in patients with severe coronary artery disease. J Cardiovasc Magn Reson. 2010;12:6.PubMedGoogle Scholar
  134. 134.
    Bolli R, Chugh AR, D’Amario D, Loughran JH, Stoddard MF, Ikram S, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011;378:1847–57.PubMedGoogle Scholar
  135. 135.
    Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C, et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation. 2003;107:461–8.PubMedGoogle Scholar
  136. 136.
    Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, et al. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation. 2010;121:293–305.PubMedGoogle Scholar
  137. 137.
    Kobayashi T, Hamano K, Li TS, Katoh T, Kobayashi S, Matsuzaki M, et al. Enhancement of angiogenesis by the implantation of self bone marrow cells in a rat ischemic heart model. J Surg Res. 2000;89:189–95.PubMedGoogle Scholar
  138. 138.
    Schneider C, Jaquet K, Geidel S, Rau T, Malisius R, Boczor S, et al. Transplantation of bone marrow-derived stem cells improves myocardial diastolic function: strain rate imaging in a model of hibernating myocardium. J Am Soc Echocardiogr. 2009;22:1180–9.PubMedGoogle Scholar
  139. 139.
    Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167:989–97.PubMedGoogle Scholar
  140. 140.
    Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Paczkowska E, Ciosek J, et al. Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J Am Coll Cardiol. 2009;53:1–9.PubMedGoogle Scholar
  141. 141.
    Dai W, Kloner RA. Bone marrow-derived cell transplantation therapy for myocardial infarction: lessons learned and future questions. Am J Transplant. 2011;11:2297–301.PubMedGoogle Scholar
  142. 142.
    Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–5.PubMedGoogle Scholar
  143. 143.
    Goodell MA, Jackson KA, Majka SM, Mi T, Wang H, Pocius J, et al. Stem cell plasticity in muscle and bone marrow. Ann N Y Acad Sci. 2001;938:208–18. discussion 18–20.PubMedGoogle Scholar
  144. 144.
    Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107:1395–402.PubMedGoogle Scholar
  145. 145.
    Wojakowski W, Kucia M, Zuba-Surma E, Jadczyk T, Ksiazek B, Ratajczak MZ, et al. Very small embryonic-like stem cells in cardiovascular repair. Pharmacol Ther. 2011;129:21–8.PubMedGoogle Scholar
  146. 146.
    Deindl E, Zaruba MM, Brunner S, Huber B, Mehl U, Assmann G, et al. G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis. FASEB J. 2006;20:956–8.PubMedGoogle Scholar
  147. 147.
    Theiss HD, Vallaster M, Rischpler C, Krieg L, Zaruba MM, Brunner S, et al. Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis. Stem Cell Res. 2011;7:244–55.PubMedGoogle Scholar
  148. 148.
    Jujo K, Hamada H, Iwakura A, Thorne T, Sekiguchi H, Clarke T, et al. CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction. Proc Natl Acad Sci USA. 2010;107:11008–13.PubMedGoogle Scholar
  149. 149.
    Hu CH, Li ZM, Du ZM, Zhang AX, Rana JS, Liu DH, et al. Expanded human cord blood-derived endothelial progenitor cells salvage infarcted myocardium in rats with acute myocardial infarction. Clin Exp Pharmacol Physiol. 2010;37:551–6.PubMedGoogle Scholar
  150. 150.
    Ma N, Stamm C, Kaminski A, Li W, Kleine HD, Muller-Hilke B, et al. Human cord blood cells induce angiogenesis following myocardial infarction in NOD/scid-mice. Cardiovasc Res. 2005;66:45–54.PubMedGoogle Scholar
  151. 151.
    Mauritz C, Martens A, Rojas SV, Schnick T, Rathert C, Schecker N, et al. Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction. Eur Heart J. 2011;32:2634–41.PubMedGoogle Scholar
  152. 152.
    Malliaras K, Kreke M, Marban E. The stuttering progress of cell therapy for heart disease. Clin Pharmacol Ther. 2011;90:532–41.PubMedGoogle Scholar
  153. 153.
    Charwat S, Gyongyosi M, Lang I, Graf S, Beran G, Hemetsberger R, et al. Role of adult bone marrow stem cells in the repair of ischemic myocardium: current state of the art. Exp Hematol. 2008;36:672–80.PubMedGoogle Scholar
  154. 154.
    Liu Z, Gerdes AM. Influence of hypothyroidism and the reversal of hypothyroidism on hemodynamics and cell size in the adult rat heart. J Mol Cell Cardiol. 1990;22:1339–48.PubMedGoogle Scholar
  155. 155.
    Chilian WM, Wangler RD, Peters KG, Tomanek RJ, Marcus ML. Thyroxine-induced left ventricular hypertrophy in the rat. Anatomical and physiological evidence for angiogenesis. Circ Res. 1985;57:591–8.PubMedGoogle Scholar
  156. 156.
    Tomanek RJ, Connell PM, Butters CA, Torry RJ. Compensated coronary microvascular growth in senescent rats with thyroxine-induced cardiac hypertrophy. Am J Physiol. 1995;268:H419–25.PubMedGoogle Scholar
  157. 157.
    Tomanek RJ, Doty MK, Sandra A. Early coronary angiogenesis in response to thyroxine: growth characteristics and upregulation of basic fibroblast growth factor. Circ Res. 1998;82:587–93.PubMedGoogle Scholar
  158. 158.
    Tomanek RJ, Busch TL. Coordinated capillary and myocardial growth in response to thyroxine treatment. Anat Rec. 1998;251:44–9.PubMedGoogle Scholar
  159. 159.
    Wang X, Zheng W, Christensen LP, Tomanek RJ. DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary arteriolar growth. Am J Physiol Heart Circ Physiol. 2003;284:H613–8.PubMedGoogle Scholar
  160. 160.
    Zheng W, Weiss RM, Wang X, Zhou R, Arlen AM, Lei L, et al. DITPA stimulates arteriolar growth and modifies myocardial postinfarction remodeling. Am J Physiol Heart Circ Physiol. 2004;286:H1994–2000.PubMedGoogle Scholar
  161. 161.
    Laperche T, Logeart D, Cohen-Solal A, Gourgon R. Potential interests of heart rate lowering drugs. Heart. 1999;81:336–41.PubMedGoogle Scholar
  162. 162.
    Quyyumi AA, Wright CA, Mockus LJ, Fox KM. Mechanisms of nocturnal angina pectoris: importance of increased myocardial oxygen demand in patients with severe coronary artery disease. Lancet. 1984;1:1207–9.PubMedGoogle Scholar
  163. 163.
    Panza JA, Diodati JG, Callahan TS, Epstein SE, Quyyumi AA. Role of increases in heart rate in determining the occurrence and frequency of myocardial ischemia during daily life in patients with stable coronary artery disease. J Am Coll Cardiol. 1992;20:1092–8.PubMedGoogle Scholar
  164. 164.
    Lei L, Zhou R, Zheng W, Christensen LP, Weiss RM, Tomanek RJ. Bradycardia induces angiogenesis, increases coronary reserve, and preserves function of the postinfarcted heart. Circulation. 2004;110:796–802.PubMedGoogle Scholar
  165. 165.
    Dedkov EI, Zheng W, Christensen LP, Weiss RM, Mahlberg-Gaudin F, Tomanek RJ. Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen. Am J Physiol Heart Circ Physiol. 2007;293:H590–8.PubMedGoogle Scholar
  166. 166.
    Christensen LP, Zhang RL, Zheng W, Campanelli JJ, Dedkov EI, Weiss RM, et al. Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy. Am J Physiol Heart Circ Physiol. 2009;297:H322–30.PubMedGoogle Scholar
  167. 167.
    Zhang RL, Christensen LP, Tomanek RJ. Chronic heart rate reduction facilitates cardiomyocyte survival after myocardial infarction. Anat Rec (Hoboken). 2010;293:839–48.Google Scholar
  168. 168.
    Zheng W, Seftor EA, Meininger CJ, Hendrix MJ, Tomanek RJ. Mechanisms of coronary angiogenesis in response to stretch: role of VEGF and TGF-beta. Am J Physiol Heart Circ Physiol. 2001;280:H909–17.PubMedGoogle Scholar
  169. 169.
    Zheng W, Christensen LP, Tomanek RJ. Differential effects of cyclic and static stretch on coronary microvascular endothelial cell receptors and vasculogenic/angiogenic responses. Am J Physiol Heart Circ Physiol. 2008;295:H794–800.PubMedGoogle Scholar
  170. 170.
    Seko Y, Takahashi N, Shibuya M, Yazaki Y. Pulsatile stretch stimulates vascular endothelial growth factor (VEGF) secretion by cultured rat cardiac myocytes. Biochem Biophys Res Commun. 1999;254:462–5.PubMedGoogle Scholar
  171. 171.
    Hudlicka O, Brown M, Egginton S. Angiogenesis in skeletal and cardiac muscle. Physiol Rev. 1992;72:369–417.PubMedGoogle Scholar
  172. 172.
    Tomanek RJ, Torry RJ. Growth of the coronary vasculature in hypertrophy: mechanisms and model dependence. Cell Mol Biol Res. 1994;40:129–36.PubMedGoogle Scholar
  173. 173.
    Jaquet K, Krause K, Tawakol-Khodai M, Geidel S, Kuck KH. Erythropoietin and VEGF exhibit equal angiogenic potential. Microvasc Res. 2002;64:326–33.PubMedGoogle Scholar
  174. 174.
    Tilling L, Clapp B. Erythropoietin: a future therapy for failing hearts? Heart Fail Rev. 2011;16(6):503–8.Google Scholar
  175. 175.
    Santhanam AV, d’Uscio LV, Peterson TE, Katusic ZS. Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells. Peptides. 2008;29:1451–5.PubMedGoogle Scholar
  176. 176.
    Moon C, Krawczyk M, Ahn D, Ahmet I, Paik D, Lakatta EG, et al. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci USA. 2003;100:11612–7.PubMedGoogle Scholar
  177. 177.
    van der Meer P, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA, et al. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol. 2005;46:125–33.PubMedGoogle Scholar
  178. 178.
    Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol. 2006;48:176–84.PubMedGoogle Scholar
  179. 179.
    Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J. 2007;28:2018–27.PubMedGoogle Scholar
  180. 180.
    Nishiya D, Omura T, Shimada K, Matsumoto R, Kusuyama T, Enomoto S, et al. Effects of erythropoietin on cardiac remodeling after myocardial infarction. J Pharmacol Sci. 2006;101:31–9.PubMedGoogle Scholar
  181. 181.
    Westenbrink BD, Oeseburg H, Kleijn L, van der Harst P, Belonje AM, Voors AA, et al. Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia. Cardiovasc Drugs Ther. 2008;22:265–74.PubMedGoogle Scholar
  182. 182.
    Namiuchi S, Kagaya Y, Ohta J, Shiba N, Sugi M, Oikawa M, et al. High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention. J Am Coll Cardiol. 2005;45:1406–12.PubMedGoogle Scholar
  183. 183.
    Ferrario M, Massa M, Rosti V, Campanelli R, Ferlini M, Marinoni B, et al. Early haemoglobin-independent increase of plasma erythropoietin levels in patients with acute myocardial infarction. Eur Heart J. 2007;28:1805–13.PubMedGoogle Scholar
  184. 184.
    Booth EA, Lucchesi BR. Estrogen-mediated protection in myocardial ischemia-reperfusion injury. Cardiovasc Toxicol. 2008;8:101–13.PubMedGoogle Scholar
  185. 185.
    Deschamps AM, Murphy E, Sun J. Estrogen receptor activation and cardioprotection in ischemia reperfusion injury. Trends Cardiovasc Med. 2010;20:73–8.PubMedGoogle Scholar
  186. 186.
    Lizotte E, Grandy SA, Tremblay A, Allen BG, Fiset C. Expression, distribution and regulation of sex steroid hormone receptors in mouse heart. Cell Physiol Biochem. 2009;23:75–86.PubMedGoogle Scholar
  187. 187.
    Lin J, Steenbergen C, Murphy E, Sun J. Estrogen receptor-beta activation results in S-nitrosylation of proteins involved in cardioprotection. Circulation. 2009;120:245–54.PubMedGoogle Scholar
  188. 188.
    Kaski JC. Overview of gender aspects of cardiac syndrome X. Cardiovasc Res. 2002;53:620–6.PubMedGoogle Scholar
  189. 189.
    Kaski JC. Cardiac syndrome X in women: the role of oestrogen deficiency. Heart. 2006;92 Suppl 3:iii5–9.PubMedGoogle Scholar
  190. 190.
    Peterson LR, Eyster D, Davila-Roman VG, Stephens AL, Schechtman KB, Herrero P, et al. Short-term oral estrogen replacement therapy does not augment endothelium-independent myocardial perfusion in postmenopausal women. Am Heart J. 2001;142:641–7.PubMedGoogle Scholar
  191. 191.
    Emre A, Sahin S, Erzik C, Nurkalem Z, Oz D, Cirakoglu B, et al. Effect of hormone replacement therapy on plasma lipoproteins and apolipoproteins, endothelial function and myocardial perfusion in postmenopausal women with estrogen receptor-alpha IVS1-397 C/C genotype and established coronary artery disease. Cardiology. 2006;106:44–50.PubMedGoogle Scholar
  192. 192.
    Knuuti J, Kalliokoski R, Janatuinen T, Hannukainen J, Kalliokoski KK, Koskenvuo J, et al. Effect of estradiol-drospirenone hormone treatment on myocardial perfusion reserve in postmenopausal women with angina pectoris. Am J Cardiol. 2007;99:1648–52.PubMedGoogle Scholar
  193. 193.
    Wang Y, Wang Q, Zhao Y, Gong D, Wang D, Li C, et al. Protective effects of estrogen against reperfusion arrhythmias following severe myocardial ischemia in rats. Circ J. 2010;74:634–43.PubMedGoogle Scholar
  194. 194.
    Mericli M, Nadasy GL, Szekeres M, Varbiro S, Vajo Z, Matrai M, et al. Estrogen replacement therapy reverses changes in intramural coronary resistance arteries caused by female sex hormone depletion. Cardiovasc Res. 2004;61:317–24.PubMedGoogle Scholar
  195. 195.
    Lamping KG, Christensen LP, Tomanek RJ. Estrogen therapy induces collateral and microvascular remodeling. Am J Physiol Heart Circ Physiol. 2003;285:H2039–44.PubMedGoogle Scholar
  196. 196.
    Miura S, Saku K. Regulation of angiogenesis and angiogenic factors by cardiovascular medications. Curr Pharm Des. 2007;13:2113–7.PubMedGoogle Scholar
  197. 197.
    Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, 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.PubMedGoogle Scholar
  198. 198.
    Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation. 2002;105:739–45.PubMedGoogle Scholar
  199. 199.
    Sodha NR, Chu LM, Boodhwani M, Sellke FW. Pharmacotherapy for end-stage coronary artery disease. Expert Opin Pharmacother. 2010;11:207–13.PubMedGoogle Scholar
  200. 200.
    Boodhwani M, Nakai Y, Voisine P, Feng J, Li J, Mieno S, et al. High-dose atorvastatin improves hypercholesterolemic coronary endothelial dysfunction without improving the angiogenic response. Circulation. 2006;114:I402–8.PubMedGoogle Scholar
  201. 201.
    Bouchentouf M, Williams P, Forner KA, Cuerquis J, Michaud V, Paradis P, et al. Interleukin-2 enhances angiogenesis and preserves cardiac function following myocardial infarction. Cytokine. 2011;56:732–8.PubMedGoogle Scholar
  202. 202.
    Fujita M, Sasayama S. Coronary collateral growth and its therapeutic application to coronary artery disease. Circ J. 2010;74:1283–9.PubMedGoogle Scholar
  203. 203.
    Hubel K, Dale DC, Liles WC. Therapeutic use of cytokines to modulate phagocyte function for the treatment of infectious diseases: current status of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and interferon-gamma. J Infect Dis. 2002;185:1490–501.PubMedGoogle Scholar
  204. 204.
    Kosaki K, Ando J, Korenaga R, Kurokawa T, Kamiya A. Fluid shear stress increases the production of granulocyte-macrophage colony-stimulating factor by endothelial cells via mRNA stabilization. Circ Res. 1998;82:794–802.PubMedGoogle Scholar
  205. 205.
    Buschmann IR, Hoefer IE, van Royen N, Katzer E, Braun-Dulleaus R, Heil M, et al. GM-CSF: a strong arteriogenic factor acting by amplification of monocyte function. Atherosclerosis. 2001;159:343–56.PubMedGoogle Scholar
  206. 206.
    Seiler C, Pohl T, Wustmann K, Hutter D, Nicolet PA, Windecker S, et al. Promotion of collateral growth by granulocyte-macrophage colony-stimulating factor in patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Circulation. 2001;104:2012–7.PubMedGoogle Scholar
  207. 207.
    Zbinden S, Zbinden R, Meier P, Windecker S, Seiler C. Safety and efficacy of subcutaneous-only granulocyte-macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J Am Coll Cardiol. 2005;46:1636–42.PubMedGoogle Scholar
  208. 208.
    Zbinden R, Vogel R, Meier B, Seiler C. Coronary collateral flow and peripheral blood monocyte concentration in patients treated with granulocyte-macrophage colony stimulating factor. Heart. 2004;90:945–6.PubMedGoogle Scholar
  209. 209.
    Zbinden R, Zbinden S, Meier P, Hutter D, Billinger M, Wahl A, et al. Coronary collateral flow in response to endurance exercise training. Eur J Cardiovasc Prev Rehabil. 2007;14:250–7.PubMedGoogle Scholar
  210. 210.
    Niebauer J, Hambrecht R, Marburger C, Hauer K, Velich T, von Hodenberg E, et al. Impact of intensive physical exercise and low-fat diet on collateral vessel formation in stable angina pectoris and angiographically confirmed coronary artery disease. Am J Cardiol. 1995;76:771–5.PubMedGoogle Scholar
  211. 211.
    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.PubMedGoogle Scholar
  212. 212.
    Gloekler S, Meier P, de Marchi SF, Rutz T, Traupe T, Rimoldi SF, et al. Coronary collateral growth by external counterpulsation: a randomised controlled trial. Heart. 2010;96:202–7.PubMedGoogle Scholar
  213. 213.
    Fuchs S, Baffour R, Zhou YF, Shou M, Pierre A, Tio FO, et al. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol. 2001;37:1726–32.PubMedGoogle Scholar
  214. 214.
    Tang YL, Zhao Q, Qin X, Shen L, Cheng L, Ge J, et al. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg. 2005;80:229–36. discussion 36–7.PubMedGoogle Scholar
  215. 215.
    Tang J, Xie Q, Pan G, Wang J, Wang M. Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur J Cardiothorac Surg. 2006;30:353–61.PubMedGoogle Scholar
  216. 216.
    Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11:367–8.PubMedGoogle Scholar
  217. 217.
    Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation. 2005;111:150–6.PubMedGoogle Scholar
  218. 218.
    Belmadani S, Matrougui K, Kolz C, Pung YF, Palen D, Prockop DJ, et al. Amplification of coronary arteriogenic capacity of multipotent stromal cells by epidermal growth factor. Arterioscler Thromb Vasc Biol. 2009;29:802–8.PubMedGoogle Scholar
  219. 219.
    Yin L, Ohanyan V, Pung YF, Delucia A, Bailey E, Enrick M, et al. Induction of vascular progenitor cells from endothelial cells stimulates coronary collateral growth. Circ Res. 2012;110:241–52.PubMedGoogle Scholar
  220. 220.
    Schirmer SH, van Nooijen FC, Piek JJ, van Royen N. Stimulation of collateral artery growth: travelling further down the road to clinical application. Heart. 2009;95:191–7.PubMedGoogle Scholar
  221. 221.
    Ruel M, Laham RJ, Parker JA, Post MJ, Ware JA, Simons M, et al. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J Thorac Cardiovasc Surg. 2002;124:28–34.PubMedGoogle Scholar
  222. 222.
    Kukula K, Chojnowska L, Dabrowski M, Witkowski A, Chmielak Z, Skwarek M, et al. Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD). Am Heart J. 2011;161:581–9.PubMedGoogle Scholar
  223. 223.
    Meier P, Gloekler S, de Marchi SF, Indermuehle A, Rutz T, Traupe T, et al. Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial. Circulation. 2009;120:1355–63.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Robert J. Tomanek
    • 1
  1. 1.Carver College of Medicine Cardiovascular CenterUniversity of IowaIowa CityUSA

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