Heart Failure Reviews

, Volume 22, Issue 6, pp 665–683 | Cite as

Angiogenic growth factors in myocardial infarction: a critical appraisal

  • Hemalatha Thiagarajan
  • UmaMaheswari Thiyagamoorthy
  • Iswariya Shanmugham
  • Gunadharini Dharmalingam Nandagopal
  • Anbukkarasi Kaliyaperumal


In the recent past, substantial advances have been made in the treatment of myocardial infarction (MI). Despite the impact of these positive developments, MI remains to be a leading cause of morbidity as well as mortality. An interesting hypothesis is that the development of new blood vessels (angiogenesis) or the remodeling of preexisting collaterals may form natural bypasses that could compensate for the occlusion of an epicardial coronary artery. A number of angiogenic factors are proven to be elicited during MI. Exogenous supplementation of these growth factors either in the form of recombinant protein or gene would enhance the collateral vessel formation and thereby improve the outcome after MI. The aim of this review is to describe the nature and potentials of different angiogenic factors, their expression, their efficacy in animal studies, and clinical trials pertaining to MI.


Angiogenesis Myocardial infarction Angiogenic growth factors Therapeutic angiogenesis Clinical trials 



The award of DST-Women scientist fellowship to T. Hemalatha, S. Iswariya, and D.N. Gunadharini is gratefully acknowledged.

Compliance with ethical standards

Conflict of interest

The authors T. Hemalatha, T. UmaMaheswari, S. Iswariya, D.N. Gunadharini, and K. Anbukkarasi declare that there are no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR (2016) Executive summary: heart disease and stroke statistics—2016 update. A Report from the American Heart Association Circulation 133:447–454PubMedGoogle Scholar
  2. 2.
    Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A (2010) Growing epidemic of coronary heart disease in low and middle income countries. Curr Probl Cardiol 35:72–115PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Jugdutt BI (2012) Ischemia/infarction. Heart Fail Clin 8:43–51PubMedCrossRefGoogle Scholar
  4. 4.
    Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31PubMedCrossRefGoogle Scholar
  5. 5.
    Folkman J (1995) Tumor angiogenesis. In: Mendelsohn J, Howley P, Israel M, Liotta L (eds) The molecular basis of cancer. WB Saunders, Philadelphia, pp 206–232Google Scholar
  6. 6.
    Markkanen JE, Rissanen TT, Kivela A, Yla-Herttuala S (2005) Growth factor-induced therapeutic angiogenesis and arteriogenesis in the heart—gene therapy. Cardiovasc Res 65:656–664PubMedCrossRefGoogle Scholar
  7. 7.
    Bougioukas I, Didilis V, Ypsilantis P, Giatromanolaki A, Sivridis E, Lialiaris T, Mikroulis D, Simopoulos C, Bougioukas G (2007) Intramyocardial injection of low dose basic fibroblast growth factor or vascular endothelial growth factor induces angiogenesis in the infarcted rabbit myocardium. Cardiovasc Pathol 16:63–68PubMedCrossRefGoogle Scholar
  8. 8.
    Pirolli TJ (2003) Treatment of experimental heart failure with hepatocyte growth factor. PennScience 2:22–27Google Scholar
  9. 9.
    Edelberg JM, Lee SH, Kaur M, Tang L, Feirt NM, McCabe S, Bramwell O, Wong SC, Hong MK (2002) Platelet derived endothelial cell growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heart. Circulation 105:608–613PubMedCrossRefGoogle Scholar
  10. 10.
    Yanagisawa Miwa A, Uchida Y, Nakamura F, Tomaru T, Kido H, Kamijo T, Sugimoto T, Kaji K, Utsuyama M, Kurashima C (1992) Salvage of infarcted myocardium by angiogenic action of fibroblast growth factor. Science 257:1401–1403PubMedCrossRefGoogle Scholar
  11. 11.
    Li W, Tanaka K, Ihaya A, Fujibayashi Y, Takamatsu S, Morioka K, Sasaki M, Uesaka T, Kimura T, Yamada N, Tsuda T, Chiba Y (2005) Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs. Am J Physiol Heart Circ Physiol 288:H408–H415PubMedCrossRefGoogle Scholar
  12. 12.
    Maulik N, Thirunavukkarasu M (2008) Growth factors and cell therapy in myocardial regeneration. J Mol Cell Cardiol 44:219–227PubMedCrossRefGoogle Scholar
  13. 13.
    Lewis BS, Flugelman MY, Weisz A, Keren-Tal I, Schaper W (1997) Angiogenesis by gene therapy: a new horizon for myocardial revascularization? Cardiovasc res 35:490–497PubMedCrossRefGoogle Scholar
  14. 14.
    Freedman SB, Isner JM (2002) Therapeutic angiogenesis for coronary artery disease. Ann Intern Med 136:54–71PubMedCrossRefGoogle Scholar
  15. 15.
    Rivard A, Silver M, Chen D, Murohara T, Kearney M, Magner M, Isner JM (1999) Age-dependent impairment of angiogenesis. Circulation 99:111–120PubMedCrossRefGoogle Scholar
  16. 16.
    Schultz A, Lavie L, Hochberg I, Beyar R, Stone T, Skorecki K, Lavie P, Roguin A, Levy AP (1999) Interindividual heterogeneity in the hypoxic regulation of VEGF: significance for the development of the coronary artery collateral circulation. Circulation 100:547–552PubMedCrossRefGoogle Scholar
  17. 17.
    Isner JM (2000) Tissue responses to ischemia: local and remote responses for preserving perfusion of ischemic muscle. J Clin Invest 106:615–619PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Fujii H, Xun Z, Li S, Wu J, Fazek S, Weisel R, Rakowski H, Lindner J, Li R (2009) Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice. JACC Cardiovasc Imaging 2:869–679PubMedCrossRefGoogle Scholar
  19. 19.
    Engler DA (1996) Use of vascular endothelial growth factor for therapeutic angiogenesis. Circulation 94:1496–1498PubMedCrossRefGoogle Scholar
  20. 20.
    Neufeld G, Cohen T, Genrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22PubMedGoogle Scholar
  21. 21.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309PubMedCrossRefGoogle Scholar
  22. 22.
    Conn G, Soderman DD, Schaeffer MT, Wile M, Hatcher VB, Thomas KA (1990) Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci 87:1323–1327PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Semenza GL, Agani G, Iyer N, Jiang BH, Leung S, Wiener C, Yu A (1998) Hypoxia inducible factor-1: from molecular biology to cardiopulmonary physiology. Chest 114:40S–45SPubMedCrossRefGoogle Scholar
  24. 24.
    Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW (1991) The vascular endothelial growth factor family—identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5:1806–1814PubMedCrossRefGoogle Scholar
  25. 25.
    Carmeliet P (1999) Basic concepts of (myocardial) angiogenesis: role of vascular endothelial growth factor and angiopoietin. Curr Interv Cardiol rep 1:322–335PubMedGoogle Scholar
  26. 26.
    Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, Ashare AB, Lathi K, Isner JM (1998) Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 98:2800–2804PubMedCrossRefGoogle Scholar
  27. 27.
    Kalka C, Tehrani H, Laudenberg B, Vale PR, Isner JM, Asahara T, Symes JF (2000) Mobilization of endothelial progenitor cells following gene therapy with VEGF 165 in patients with inoperable coronary disease. Ann Thorac Surg 70:829–834PubMedCrossRefGoogle Scholar
  28. 28.
    Korpisalo P, Karvinen H, Rissanen TT, Kilpijoki J, Marjomaki V, Baluk P, McDonald DM, Cao Y, Eriksson U, Alitalo K, Yia Herttuala S (2008) Vascular endothelial growth factor-A and platelet derived growth factor-B combination gene therapy prolongs angiogenic effects via recruitment of interstitial mononuclear cells and paracrine effects rather than improved pericyte coverage of angiogenic vessels. Circ res 103:1092–1099PubMedCrossRefGoogle Scholar
  29. 29.
    Furlani AP, Kalil RA, Castro I, Cañedo-Delgado A, Barra M, Prates PR, Sant'Anna RT, Nesralla IA (2009) Effects of therapeutic angiogenesis with plasmid VEGF165 on ventricular function in a canine model of chronic myocardial infarction. Rev Bras Cir Cardiovasc 24:143–149PubMedCrossRefGoogle Scholar
  30. 30.
    Lee RJ, Springer ML, Blanco-Boss W, Shaw R, Ursell PC (2000) Blau HM VEGF gene delivery to myocardium: deleterious effects of unregulated overexpression. J Am Coll Cardiol 35:306AGoogle Scholar
  31. 31.
    Wang B, Cheheltani R, Rosano J, Crabbe DL, Kiani MF (2013) Targeted delivery of VEGF to treat myocardial infarction. Adv Exp Med Biol 765:307–314PubMedCrossRefGoogle Scholar
  32. 32.
    Awada HK, Johnson NR, Wang Y (2015) Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction. J Control Release 207:7–17PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6:460–463PubMedCrossRefGoogle Scholar
  34. 34.
    Yang Y, Shi C, Hou X, Zhao Y, Chen B, Tan B, Deng Z, Li Q, Liu J, Xiao Z, Miao Q, Dai J (2015) Modified VEGF targets the ischemic myocardium and promotes functional recovery after myocardial infarction. J Control Release 213:27–35PubMedCrossRefGoogle Scholar
  35. 35.
    Henry TD, Abraham JA (2000) Review of preclinical and clinical results with vascular endothelial growth factors for therapeutic angiogenesis. Curr Interv Cardiol Rep 2:228–241PubMedGoogle Scholar
  36. 36.
    Henry TD, Rocha-Sin K, Isner JM, Kereiakes DJ, Giordano FJ, Simons M, Losordo DW, Hendel RC, Bonow RO, Eppler SM, Zioncheck TF, Holmgren EB, McCluskey ER (2001) Intracoronary administration of recombinant human vascular endothelial growth factor (rhVEGF) to patients with coronary artery disease. Am Heart J 142:872–880PubMedCrossRefGoogle Scholar
  37. 37.
    Henry TD, Annex BH, Azrin MA, McKendall GR, Willerson JT, Hendel RC, Giordano F, Klein R, Gibson M, Berman DS, Luce CA, McCluskey ER (1999) Final results of the VIVA trial of rhVEGF for human therapeutic angiogenesis (abstract). Circulation 100:I-476Google Scholar
  38. 38.
    Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, Shah PK, Willerson JT, Benza RL, Berman DS, Gibson CM, Bajamonde A, Rundle AC, Fine J, McCluskey ER (2003) The VIVA trial: vascular endothelial growth factor in ischemia or vascular angiogenesis. Circulation 107:1359–1365PubMedCrossRefGoogle Scholar
  39. 39.
    Losordo DW, Vale PR, Hendel RC, Milliken CE, Fortuin FD, Cummings N, Schatz RA, Asahara T, Isner JM, Kuntz RE (2002) 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 105:2012–2018PubMedCrossRefGoogle Scholar
  40. 40.
    Vale PR, Losordo DW, Milliken CE, McDonald MC, Ravelin LM, Curry CM, Esakof DD, Maysky M, Symes JF, Isner JM (2001) Randomized, single-blind placebo-controlled pilot study of catheter based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation 103:2138–2143PubMedCrossRefGoogle Scholar
  41. 41.
    Vale PR, Milliken CE, Fortuin D, Schatz RA, Esakof DD, Maysky M, Symes JF, Losordo DW (2000) Effective gene transfer of ph VEGF-2 for therapeutic angiogenesis in chronic myocardial ischemia as assessed by NOGA left ventricular electromechanical mapping (abstract). Circulation 102:II-689CrossRefGoogle Scholar
  42. 42.
    Rosengart TK, Lee LY, Patel SR, Sanborn TA, Parikh M, Bergman GW, Hachamovitch R, Szulc M, Kligfield PD, Okin PM, Hahn RT, Devereux RB, Post MR, Hackett NR, Foster T, Grasso TM, Lesser ML, Isom OW, Crystal RG (1999) Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 100:468–474PubMedCrossRefGoogle Scholar
  43. 43.
    Hedman M, Hartikainen J, Syvanne M, Stjernvall J, Hedman A, Kivela A, Vanninen E, Musalo H, Kauppila E, Simula S, Narvanen O, Rantala A, Peuhkurinen K, Nieminen MS, Laakso M, Yla-Herttuala Y (2003) 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 107:2677–2683PubMedCrossRefGoogle Scholar
  44. 44.
    Kastrup J, Jørgensen E, Rück A, Tägil K, Glogar D, Ruzyllo W, Bøtker HE, Dudek D, Drvota V, Hesse B, Thuesen L, Blomberg P, Gyöngyösi M, Sylvén C (2005) 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 45:982–988PubMedCrossRefGoogle Scholar
  45. 45.
    Gyöngyösi M, Khorsand A, Zamini S, Sperker W, Strehblow C, Kastrup J, Jorgensen E, Hesse B, Tägil K, Bøtker HE, Ruzyllo W, Teresiñska A, Dudek D, Hubalewska A, Rück A, Nielsen SS, Graf S, Mundigler G, Novak J, Sochor H, Maurer G, Glogar D, Sylven C (2005) 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 112:I-157–I-165CrossRefGoogle Scholar
  46. 46.
    Bokeriya LA, Golukhova EZ, Eremeeva MV, Aslanidi IP, Merzlyakov VY, Georgiev GP, Kiselev SL, Berishvili II, Vakhromeeva MN, Serov RA, Artyukhina TV, Basarab YS, Polyakova ES, Lukashkin MA (2005) Use of human VEGF(165) gene for therapeutic angiogenesis in coronary patients: first results. Bull Exp Biol Med 140:106–112PubMedCrossRefGoogle Scholar
  47. 47.
    Gao F, He T, Wang HB, Yu SQ, Yi DH, Liu WY, Cai Z (2007) A promising strategy for the treatment of ischemic heart disease: mesenchymal stem cell mediated vascular endothelial growth factor gene transfer in rats. Can J Cardiol 23:891–898PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Hagikura K, Fukuda N, Yokoyama S, Yuxin L, Kusumi Y, Matsumoto T, Ikeda Y, Kunimoto S, Takayama T, Jumabay M, Mitsumata M, Saito S, Hirayama A, Mugishima H (2010) Low invasive angiogenic therapy for myocardial infarction by retrograde transplantation of mononuclear cells expressing the VEGF gene. Int J Cardiol 142:56–64PubMedCrossRefGoogle Scholar
  49. 49.
    Deuse T, Peter C, Fedak WM, Doyle T, Reichenspurner H, Zimmermann WH, Eschenhagen T, Stein W, Wu JC, Robbins RC, Schrepfer S (2009) Hepatocyte growth factor or vascular endothelial growth factor gene transfer maximizes mesenchymal stem cell-based myocardial salvage after acute myocardial infarction. Circulation 120(11 Suppl):S247–S254PubMedCrossRefGoogle Scholar
  50. 50.
    Esch F, Ueno N, Baird A, Hill F, Denoroy L, Ling N, Gospodarowicz D, Guillemin R (1985) Primary structure of bovine brain acidic fibroblast growth factor. Biochem Biophys Res Commun 133:554–562PubMedCrossRefGoogle Scholar
  51. 51.
    Folkman J, Klagsburn M (1987) Angiogenic factors. Science 235:442–447PubMedCrossRefGoogle Scholar
  52. 52.
    Kuwabara K, Ogawa S, Matsumoto M, Koga S, Clauss S, Pinsky DJ, Lyn P, Leavy J, Witte L, Joseph-Silverstein J (1995) Hypoxia mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Nat Acad Sci USA 92:4606–4610PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Banai S, Jaklitsch MT, Casscells W, Shou M, Shrivastav S, Correa R, Epstein SE, Unger EF (1991) Effects of acidic fibroblast growth factor on normal and ischemic myocardium. Circ res 69:76–85PubMedCrossRefGoogle Scholar
  54. 54.
    Gospodarowicz D (1989) Fibroblast growth factor. Crit rev Oncog 1:1–26PubMedGoogle Scholar
  55. 55.
    Mergia A, Eddy R, Abraham JA, Fiddes JC, Shows TB (1986) The genes or basic and acidic fibroblast growth factors are on different human chromosomes. Biochem Biophys Res Commun 138:644–651PubMedCrossRefGoogle Scholar
  56. 56.
    Florkiewicz RZ, Sommer A (1989) Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons. Proc Natl Acad Sci U S a 86:3978–3981PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Wadzinski MG, Folkman J, Sasse J, Devey K, Ingber D, Klagsbrun M (1987) Heparin-binding angiogenesis factors: detection by immunological methods. Clin Physiol Biochem 5:200–209PubMedGoogle Scholar
  58. 58.
    Klagsbrun M (1989) The fibroblast growth factor family: structural and biological properties. Prog Growth Factor Res 1:207–235PubMedCrossRefGoogle Scholar
  59. 59.
    Xu X, Weinstein M, Li C, Deng C (1999) Fibroblast growth factor receptors (FGFRs) and their roles in limb development. Cell Tissue Res 296:33–43PubMedCrossRefGoogle Scholar
  60. 60.
    Losordo DW, Dimmeler S (2004) Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I: angiogenic cytokines. Circulation 109:2487–2491PubMedCrossRefGoogle Scholar
  61. 61.
    Goto F, Goto K, Weindel K, Folkman J (1993) Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Investig 69:508–517PubMedGoogle Scholar
  62. 62.
    Asahara T, Bauters C, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM (1995) Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation 92(Suppl 9):II365–II371PubMedCrossRefGoogle Scholar
  63. 63.
    Felmeden DC, Blann AD, Lip GYH (2003) Angiogenesis: basic pathophysiology and implications for disease. Eur Heart J 24:586–603PubMedCrossRefGoogle Scholar
  64. 64.
    Zhao T, Zhao W, Chen Y, Ahokas RA, Sun Y (2011) Acidic and basic fibroblast growth factors involved in cardiac angiogenesis following infarction. Int J Cardiol 152:307–313PubMedCrossRefGoogle Scholar
  65. 65.
    Goncalves LM (2000) Angiogenic growth factors: potential new treatment for acute myocardial infarction? Cardiovasc Res 45:294–302PubMedCrossRefGoogle Scholar
  66. 66.
    Nakajima H, Sakakibara Y, Tambara K, Iwakura A, Doi K, Marui A, Ueyama K, Ikeda T, Tabata Y, Komeda M (2004) Therapeutic angiogenesis by the controlled release of basic fibroblast growth factor for ischemic limb and heart injury: toward safety and minimal invasiveness. J Artif Organs 7:58–61PubMedCrossRefGoogle Scholar
  67. 67.
    Kawasuji M, Nagamine H, Ikeda M, Sakakibara N, Takemura H, Fujii S, Watanabe Y (2000) Therapeutic angiogenesis with intramyocardial administration of basic fibroblast growth factor. Ann Thorac Surg 69:1155–1161PubMedCrossRefGoogle Scholar
  68. 68.
    Garbern JC, Minami E, Stayton PS, Murry CE (2011) Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium. Biomaterials 32:2407–2416PubMedCrossRefGoogle Scholar
  69. 69.
    Liu XC, Zhao J, Wang Y, Liu TJ, Lü F, He GW (2010) Heparin- and basic fibroblast growth factor-incorporated stent: a new promising method for myocardial revascularization. J Surg Res 164:204–213PubMedCrossRefGoogle Scholar
  70. 70.
    Yang Y, Gruwel ML, Dreessen de Gervai P, Sun J, Jilkina O, Gussakovsky E, Kupriyanov V (2012) MRI study of cryoinjury infarction in pig hearts: i. Effects of intrapericardial delivery of bFGF/VEGF embedded in alginate beads. NMR Biomed 25:177–188PubMedCrossRefGoogle Scholar
  71. 71.
    Chu H, Chen CW, Huard J, Wang Y (2013) The effect of a heparin-based coacervate of fibroblast growth factor-2 on scarring in the infarcted myocardium. Biomaterials 34:1747–1756PubMedCrossRefGoogle Scholar
  72. 72.
    Schumacher B, Peter P, von Specht BU, Stegmann T (1998) Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation 97:645–650PubMedCrossRefGoogle Scholar
  73. 73.
    Stegmann TJ, Hopppert T, Schneider A, Gemeinhardt S, Kocher M, Ibing R, Strupp G (2000) Induction of myocardial neoangiogenesis by human growth factors. A new Therapeutic Approach in Coronary Heart Disease Herz 25:589–599PubMedGoogle Scholar
  74. 74.
    Sellke FW, Laham RJ, Edelman ER, Pearlman JD, Simons M (1998) Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results. Ann Thoracic Surg 65:1540–1544CrossRefGoogle Scholar
  75. 75.
    Laham RJ, Sellke FW, Edelman ER, Pearlman JD, Ware JA, Brown DL, Gold JP, Simons M (1999) Local perivasuclar delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery; results of a phase I randomised, double-blind placebo-controlled trial. Circulation 100:1865–1871PubMedCrossRefGoogle Scholar
  76. 76.
    Laham RJ, Chronos NA, Pike M, Leimbach ME, Udelson JE, Pearlman JD, Pettigrew RI, Whitehouse MJ, Yoshizawa C, Simons M (2000) Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic disease; results of a phase I open-label dose escalation study. J Am Coll Cardiol 36:2132–2139PubMedCrossRefGoogle Scholar
  77. 77.
    Unger EF, Goncalves I, Epstein SE, Chew EY, Trapnell CB, Cannon RO, Quyyumi AA (2000) Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am J Cardiol 85:1414–1419PubMedCrossRefGoogle Scholar
  78. 78.
    Kleiman NS, Califf RM (2000) Results from late-breaking clinical trials sessions at ACCIS 2000 and ACC 2000. American College of Cardiology. J Am Coll Cardiol 36:310–325PubMedCrossRefGoogle Scholar
  79. 79.
    Grines CL (2001) Adenovirus FGF angiogenic therapy (AGENT) trial for stable angina. In: Late-breaking clinical trial, American College of Cardiology 50th Annual Scientific sessions, 18–21 March.Google Scholar
  80. 80.
    Grines CL, Watkins MW, Helmer G, Penny W, Brinker J, Marmur JD, West A, Rade JJ, Marrott P, Hammond HK, Engler RL (2002) Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105:1291–1297PubMedCrossRefGoogle Scholar
  81. 81.
    Grines C, Rubanyi GM, Kleiman NS, Marrott P, Watkins MW (2003) Angiogenic gene therapy with adenovirus 5 fibroblast growth factor-4 (Ad5FGF-4): a new option for the treatment of coronary artery disease. Am J Cardiol 92:24N–31NPubMedCrossRefGoogle Scholar
  82. 82.
    Henry TD, Grines CL, Watkins MW, Dib N, Barbeau G, Moreadith R, Andrasfay T, Engler RL (2007) 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 50:1038–1046PubMedCrossRefGoogle Scholar
  83. 83.
    Miyazawa K, Tsubouchi H, Naka D, Takahashi K, Okigaki M, Arakaki N, Nakayama H, Hirono S, Sakiyama O, Gohda E, Daikuhara Y, Kitamura N (1989) Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun 163:967–973Google Scholar
  84. 84.
    Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Shimizu S (1989) Molecular cloning and expression of human hepatocyte growth factor. Nature (London) 342:440–443CrossRefGoogle Scholar
  85. 85.
    Grant DS, Kleinman HK, Goldberg ID, Bharava MM, Nickoloff BJ, Kinsella JL, Polverini P, Rosen EM (1993) Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci U S a 90:1937–1941PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Matsumori A, Furukawa Y, Hashimoto T, Ono K, Shioi T, Okada M, Iwasaki A, Nishio R, Sasayama S (1996) Increased circulating hepatocyte growth factor in the early stage of acute myocardial infarction. Biochem Biophys Res Commun 221:391–395PubMedCrossRefGoogle Scholar
  87. 87.
    Sato T, Yoshinouchi T, Sakamoto T, Fujieda H, Murao S, Sato H, Kobayashi H, Ohe T (1997) Hepatocyte growth factor (HGF): a new biochemical marker for acute myocardial infarction. Heart Vessel 12:241–246CrossRefGoogle Scholar
  88. 88.
    He JG, Wu JL, Yan L, Zhang DS, Tan XY, Qi RD, Guo YH (2008) Hepatocyte growth factor and granulocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy. Cytotherapy 10:857–867PubMedCrossRefGoogle Scholar
  89. 89.
    Ahmet I, Sawa Y, Yamauchi T, Matsuda H (2003) Gene transfer of hepatocyte growth factor improves angiogenesis and function of chronic ischemic myocardium in canine heart. Ann Thoracic Surg 75:1283–1287CrossRefGoogle Scholar
  90. 90.
    Saeed M, Saloner D, Do L, Wilson M, Martin A (2011) Cardiovascular magnetic resonance imaging in delivering and evaluating the efficacy of hepatocyte growth factor gene in chronic infarct scar. Cardiovasc Revasc med 12:111–122PubMedCrossRefGoogle Scholar
  91. 91.
    Xin X, Yang S, Ingle G, Zlot C, Ranell L, Kowalski J, Schwall R, Ferrara N, Gerristen ME (2001) Hepatocyte growth factor enhances vascular endothelial growth factor induced angiogenesis in vitro and in vivo. Am J Pathol 158:1111–1120PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Ueda H, Nakamuraa T, Matsumotoa K, Sawab Y, Matsudab H, Namakura T (2001) A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats. Cardiovasc res 51:41–50PubMedCrossRefGoogle Scholar
  93. 93.
    Funatsu T, Sawa Y, Ohtake S, Takehashi T, Matsumiya G, Matsuura N, Nakamura T, Matsuda H (2002) Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor. J Thorac Cardiovasc Surg 124:1099–1105PubMedCrossRefGoogle Scholar
  94. 94.
    Duan HF, Wu CT, Wu DL, Lu Y, Liu HJ, Ha XQ, Zhan QW, Wand H, Jia XX, Wan LS (2003) Treatment of myocardial ischemia with bone marrow derived mesenchymal stem cells overexpressing hepatocyte growth factor. Mol Ther 8:467–474PubMedCrossRefGoogle Scholar
  95. 95.
    Konda I, Ohmori K, Oshita A, Takeuchi H, Fuke S, Shinomya K, Noma T, Namba T, Kohna M (2004) Treatment of acute myocardial infarction by hepatocyte growth factor gene transfer. The first demonstration of myocardial transfer of a “functional” gene using ultrasonic microbubble destruction. J Am Coll Cardiol 44:644–653CrossRefGoogle Scholar
  96. 96.
    Perin EC, Silva GV, Vela DC, Zheng Y, Baimbridge F, Gahremanpour A, Quan X, Hahn W, Kim J, Wood K, Kitamura M (2011) Human hepatocyte growth factor (VM202) gene therapy via transendocardial injection in a pig model of chronic myocardial ischemia. J Card Fail 17:601–611PubMedCrossRefGoogle Scholar
  97. 97.
    Lu F, Zhao X, Wu J, Cui Y, Mao Y, Chen K, Yuan Y, Gong D, Xu Z, Huang S (2013) MSCs transfected with hepatocyte growth factor or vascular endothelial growth factor improve cardiac function in the infarcted porcine heart by increasing angiogenesis and reducing fibrosis. Int J Cardiol 167:2524–2532PubMedCrossRefGoogle Scholar
  98. 98.
    Zhao L, Liu X, Zhang Y, Liang X, Ding Y, Xu Y, Fang Z, Zhang F (2016) Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction. Exp Cell Res 344:30–39PubMedCrossRefGoogle Scholar
  99. 99.
    Raines EW, Bowen-Pope DF, Ross R (1990) Peptide growth factors and their receptors II. In: Sporn MB, Roberts AB (eds.) Springer Verlag, Berlin, pp. 173–262.Google Scholar
  100. 100.
    Heldin C (1992) Structural and functional studies on platelet-derived growth factor. EMBO J 11:4251–4259PubMedPubMedCentralGoogle Scholar
  101. 101.
    Raines EW, Ross R (1992) Compartmentalization of PDGF on extracellular binding sites dependent on exon-6-encoded sequences. J Cell Biol 116:533–543PubMedCrossRefGoogle Scholar
  102. 102.
    Welsh CL (1994) Platelet-derived growth factor receptor signals. J Biol Chem 269:32023–32026Google Scholar
  103. 103.
    Seifert RA, Hart CE, Phillips PE, Forstrom JW, Ross R, Murray MJ, Bowen Pope DF (1989) Two different subunits associate to create isoform-specific platelet-derived growth factor receptors. J Biol Chem 264:8771–8778PubMedGoogle Scholar
  104. 104.
    Battegay EJ, Thommen R, Humar R (1996) Platelet-derived growth factor and angiogenesis. Trends Glycosci Glycotechnol 8:231–225CrossRefGoogle Scholar
  105. 105.
    Kourembanas S, Hannan RL, Faller DV (1990) Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J Clin Invest 86:670–674PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Hart CE, Bailey M, Curtis DA, Osborn S, Raines EW, Ross R, Forstrom JW (1990) Purification of PDGF-AB and PDGF-BB from human platelet extracts and identification of all three PDGF dimers in human platelets. Biochemistry 29:166–172PubMedCrossRefGoogle Scholar
  107. 107.
    Khouri RK, Hong SP, Deune EG, Tarpley JE, Song SZ, Serdar CM, Pierce GF (1994) De novo generation of permanent neovascularized soft tissue appendages by platelet-derived growth factor. J Clin Invest 94:1757–1763PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Benjamin L, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125:1591–1598PubMedGoogle Scholar
  109. 109.
    Yu J, Moon A, Kim HR (2001) Both platelet-derived growth factor receptor (PDGFR)-alpha and PDGFR-beta promote murine fibroblast cell migration. Biochem Biophys Res Commun 282:697–700PubMedCrossRefGoogle Scholar
  110. 110.
    Hirschi KK, D’Amore PA (1997) Control of angiogenesis by the pericyte: molecular mechanisms and significance. EXS 79:419–428PubMedGoogle Scholar
  111. 111.
    Zhao W, Zhao T, Huang V, Chen Y, Ahokas RA, Sun Y (2011b) Platelet-derived growth factor involvement in myocardial remodeling following infarction. J Mol Cell Cardiol 51:830–838PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245PubMedCrossRefGoogle Scholar
  113. 113.
    Yla-Herttuala S, Alitalo K (2003) Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 9:694–701PubMedCrossRefGoogle Scholar
  114. 114.
    Hao X, Silva EA, Manson-Brober A, Grinnemo KH, Siddiqui AJ, Dellren G, Wardell E, Brodin AL, Mooney DJ, Sylven C (2007) Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with aliginate hydrogels after myocardial infarction. Cardiovasc res 75:178–185PubMedCrossRefGoogle Scholar
  115. 115.
    Zymek P, Bujak M, Chatila K, Cieslak A, Thakker G, Entman ML, Frangogiannis NG (2006) The role of platelet-derived growth factor signaling in healing myocardial infarcts. J Am Coll Cardiol 48:2315–2323PubMedCrossRefGoogle Scholar
  116. 116.
    Miyazono K, Okabe T, Urabe A, Takaku F, Heldin CH (1987) Purification and properties of an endothelial cell growth factor from human platelets. J Biol Chem 262:4098–4103PubMedGoogle Scholar
  117. 117.
    Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH (1989) Identification of angiogenic activity and the cloning and expression of platelet derived endothelial cell growth factor. Nature 338:557–562PubMedCrossRefGoogle Scholar
  118. 118.
    Ikeda R, Tajitsu Y, Iwashita K, Che XF, Yoshida K, Ushiyama M, Furukawa T, Komatsu M, Yamaguchi T, Shibayama Y, Yamamoto M, Zhao HY, Arima J, Takeda Y, Akiyama S, Yamada K (2008) Thymidine phosphorylase inhibits the expression of proapoptotic protein BNIP3. Biochem Biophys Res Commun 370:220–224PubMedCrossRefGoogle Scholar
  119. 119.
    Li W, Chiba Y, Kimura T, Morioka K, Uesaka T, Ihaya A, Muraoka R (2001) Transmyocardial laser revascularisation induced angiogenesis correlated with the expression of matrix metalloproteinases and platelet derived endothelial cell growth factor. Eur J Cardiothorac Surg 19:156–163PubMedCrossRefGoogle Scholar
  120. 120.
    Miyadera K, Sumizawa T, Haraguchi M, Yoshida H, Konstanty W, Yamada Y, Akiyama S (1995) Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer res 55:1687–1690PubMedGoogle Scholar
  121. 121.
    Moghaddam A, Zhang HT, Fan TP, Hu DE, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R (1995) Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci U S a 92:998–1002PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Usuki K, Saras J, Waltenberger J, Miyazono K, Pierce G, Thomason A, Heldin CH (1992) Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun 1M4:1311–1316CrossRefGoogle Scholar
  123. 123.
    Haraguchi M, Miyadera K, Uemura K, Sumizawa T, Furukawa T, Yamada K, Akiyama S, Yamada Y (1994) Angiogenic activity of enzymes. Nature 368:198PubMedCrossRefGoogle Scholar
  124. 124.
    Griffiths L, Dachs GU, Bicknell R, Hariis AL, Stratford IJ (1997) The influence of oxygen tension and pH on the expression of platelet derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivo. Cancer Res 57:570–572PubMedGoogle Scholar
  125. 125.
    Brown NS, Bicknell R (1998) Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis. Biochem J 334(Pt 1):1–8PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Ignatescu MC, Gharehbaghi-Schnell EG, Hassan A, Rezaie-Majd S, Korschineck I, Schleef RR, Glogar HD, Lang IM (1999) Expression of the angiogenic protein platelet derived endothelial cell growth factor in coronary artherosclerotic plaques: in vivo correlation of lesional microvessel density and constrictive vascular remodeling. Arterioscler Thromb Vasc Biol 19:2340–2347PubMedCrossRefGoogle Scholar
  127. 127.
    Hemalatha T, Balachandran C, Murali Manohar B, Nayeem M, Subramaniam S, Sharma HS, Puvanakrishnan R (2010) Myocardial expression of PDECGF is associated with extracellular matrix remodeling in experimental myocardial infarction in rats. Biochem Cell Biol 88:491–503PubMedCrossRefGoogle Scholar
  128. 128.
    Yamada N, Li W, Ihaya A, Kimura T, Morioka K, Ueska T, Takamori A, Hana M, Tanabe S, Tanaka K (2006) Platelet-derived endothelial cell growth factor gene therapy for limb ischemia. J Vasc Surg 44:1322–1328PubMedCrossRefGoogle Scholar
  129. 129.
    Li W, Tanaka K, Morioka K, Uesaka T, Yamada N, Takamori A, Handa M, Tanabe S, Ihaya A (2005b) Thymidine phosphorylase gene transfer inhibits vascular smooth muscle cell proliferation by upregulating heme oxygenase-1 and p27KIP1. Arterioscler Thromb Vasc Biol 25:1370–1375PubMedCrossRefGoogle Scholar
  130. 130.
    Li W, Tanaka K, Morioka K, Takamori A, Handa M, Yamada N, Ihaya A (2008) Long term effect of gene therapy for chronic ischemic myocardium using platelet derived endothelial cell growth factor in dogs. J Gene Med 10:412–420PubMedCrossRefGoogle Scholar
  131. 131.
    Hemalatha T, Tiwari M, Balachandran C, Manohar BM, Puvanakrishnan R (2009) Platelet derived endothelial cell growth factor mediates angiogenesis and antiapoptosis in rat aortic endothelial cells. Biochem Cell Biol 87:883–893PubMedCrossRefGoogle Scholar
  132. 132.
    Schuster SJ, Koury ST, Bohler M, Salceda S, Caro J (1992) Cellular sites of extrarenal and renal erythropoietin production in anaemic rats. Br J Haematol 81:153–159PubMedCrossRefGoogle Scholar
  133. 133.
    Ebert BL, Bunn HF (1999) Regulation of the erythropoietin gene. Blood 94:1864–1877PubMedGoogle Scholar
  134. 134.
    Hellwig-Burgel T, Rutkowski K, Metzen E, Fandrey J, Jelkmann W (1999) Interleukin-1β and tumor necrosis factor-α stimulate DNA binding of hypoxia inducible factor-1. Blood 94:1561–1567PubMedGoogle Scholar
  135. 135.
    Jelkmann W, Wagner K (2004) Beneficial and ominous aspects of the pleiotropic action of erythropoietin. Ann Hematol 83:673–686PubMedCrossRefGoogle Scholar
  136. 136.
    Anagnostou A (1994) Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci U S a 91:3974–3978PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Chong ZZ, Kang JQ, Maiese K (2002) Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 106:2973–2979PubMedCrossRefGoogle Scholar
  138. 138.
    Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, Zweier JL, Semenza GL (2003) Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia reperfusion injury. Circulation 108:79–85PubMedCrossRefGoogle Scholar
  139. 139.
    Shi Y, Rafiee P, Su J, Pritchard KA Jr, Tweddell JS, Baker JE (2004) Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels. Basic res Cardiol 99:173–182PubMedCrossRefGoogle Scholar
  140. 140.
    Hanlon PR, Fu P, Wright GL, Steenbergen C, Arcasoy MO, Murphy E (2005) Mechanisms of erythropoietin-mediated cardioprotection during ischemia reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling. FASEB j 19:1323–1325PubMedGoogle Scholar
  141. 141.
    Wald M, Gutnisky A, Borda E, Sterin-Borda L (1995) Erythropoietin modified the cardiac action of ouabain in chronically anaemic-uraemic rats. Nephron 71:190–196PubMedCrossRefGoogle Scholar
  142. 142.
    Porat O, Neumann D, Zamir O, Nachshon S, Feigin E, Cohen J, Zamir N (1996) Erythropoietin stimulates atrial natriuretic peptide secretion from adult rat cardiac atrium. J Pharmacol Exp Ther 276:1162–1168PubMedGoogle Scholar
  143. 143.
    Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, Thompson RB, Petrofski JA, Annex BH, Stamler JS, Koch WJ (2003) A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112:999–1007PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Parsa CJ, Kim J, Riel RU, Pascal LS, Thompson RB, Petrofski JA, Matsumoto A, Stamler JS, Koch WJ (2004) Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J Biol Chem 279:20655–20662PubMedCrossRefGoogle Scholar
  145. 145.
    Bullard AJ, Govewalla P, Yellon DM (2005) Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol 100:397–403PubMedCrossRefGoogle Scholar
  146. 146.
    Hirata A, Minamino T, Asanuma H, Sanada S, Fujita M, Tsukamoto O, Wakeno M, Myoishi M, Okada K, Koyama H, Komamura K, Takashima S, Shinozaki Y, Mori H, Tomoike H, Hori M, Kitakaze M (2005) Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts. Cardiovasc Drugs Ther 19:33–40PubMedCrossRefGoogle Scholar
  147. 147.
    Moon C, Krawczyk M, Ahn D, Ahmet I, Paik D, Lakatta E, Talan MI (2003) Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci U S A 100:11612–11617PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Darvaas J, Koster J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG (2007) Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J 28:2018–2027PubMedCrossRefGoogle Scholar
  149. 149.
    Van der Meer P, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker R (2005) Erythropoietin induced neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J am Coll Cardiol 46:125–133PubMedCrossRefGoogle Scholar
  150. 150.
    Brunner S, Winoradow J, Huber BC, Micheal Z, Fischer R, Assmann G, Herbach N, Wanke R, Mueller-Hoecker J, Franz WM (2009) Erythropoietin administration after myocardial infarction in mice attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow-derived progenitor cell via the CXCR-4/SDF-1 axis. FASEB j 23:351–361PubMedCrossRefGoogle Scholar
  151. 151.
    Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, Tsukamoto O, Okada K, Koyama H, Komamura K, Takashima S, Shinozaki Y, Mori H, Shiraga M, Kitakaze M, Hori M (2006) Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol 48:176–184PubMedCrossRefGoogle Scholar
  152. 152.
    Broberg AM, Grinnemo KH, Genead R, Danielsson C, Andersson AB, Wärdell E, Sylvén C (2008) Erythropoietin has an antiapoptotic effect after myocardial infarction and stimulates in vitro aortic ring sprouting. Biochem Biophys Res Commun 371:75–78PubMedCrossRefGoogle Scholar
  153. 153.
    Bagla AG, Ercan E, Asgun HF, Ickin M, Ercan F, Yavuz O, Bagla S, Kaplan A (2013) Experimental acute myocardial infarction in rats: HIF-1α, caspase-3, erythropoietin and erythropoietin receptor expression and the cardioprotective effects of two different erythropoietin doses. Acta Histochem 115:658–668PubMedCrossRefGoogle Scholar
  154. 154.
    Van Veldhuisen DJ, Dickstein K, Cohen-Solal A, Lok DJ, Wasserman SM, Baker N, Rosser D, Cleland JG, Ponikowski P (2007) Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anemia. Eur Heart J 28:2208–2216PubMedCrossRefGoogle Scholar
  155. 155.
    Lipsic E, van der Meer P, Voors AA (2006) A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction: a randomized feasibility and safety study. Cardiovasc Drugs Ther 20:135–141PubMedCrossRefGoogle Scholar
  156. 156.
    Lipsic E, Schoemaker R, van der Meer P, Voors AA, van Veldhuisen DJ, van Gilst WH (2006) Protective effects of erythropoietin in cardiac ischemia; from bench to bedside. J Am Coll Cardiol 48:2161–2167PubMedCrossRefGoogle Scholar
  157. 157.
    Ferrario M, Arbustini E, Massa M, Rosti V, Marziliano N, Raineri C, Campanelli R, Bertoletti A, De Ferrari GM, Klersy C, Angoli L, Bramucci E, Marinoni B, Ferlini M, Moretti E, Raisaro A, Repetto A, Schwartz PJ, Tavazzi L (2011) High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study. Int J Cardiol 147:124–131PubMedCrossRefGoogle Scholar
  158. 158.
    Rookmaaker MB, Verhaar MC, Loomans CJ, Verloop R, Peters E, Westerweel PE, Murohara T, Staal FJ, Van Zonneveld AJ, Koolwijk P, Rabelink TJ, Van Hinsbergh VW (2005) CD34+ cells home, proliferate, and participate in capillary formation, and in combination with CD34-cells enhance tube formation in a 3-dimensional matrix. Arterio Thromb Vasc Biol 25:1–8CrossRefGoogle Scholar
  159. 159.
    Ali-Hassan-Sayegh S, Mirhosseini SJ, Tahernejad M, Mahdavi P, Haddad F, Shahidzadeh A, Lotfaliani MR, Sedaghat-Hamedani F, Kayvanpour E, Weymann A, Sabashnikov A, Popov AF (2015) Administration of erythropoietin in patients with myocardial infarction: does it make sense? An updated and comprehensive meta-analysis and systematic review. Cardiovasc Revasc med 16:179–189PubMedCrossRefGoogle Scholar
  160. 160.
    Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for TIE2 that disrupts in vivo angiogenesis. Science 277:55–60PubMedCrossRefGoogle Scholar
  161. 161.
    Valenzuela DM, Griffith JA, Rojass J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland NG, Gilbert DJ, Jenkins NA, Huang T, Papadopoulos N, Maisonpierre PC, Davis S, Yancopoulos GD (1999) Angiopoietin 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci U S a 96:1904–1909PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Asahara T, Chen D, Takahashi T, Fujikawa K, Kearnery M, Magner M, Yancopoulos GD, Isner JM (1998) Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularisation. Circ Res 83:233–240PubMedCrossRefGoogle Scholar
  163. 163.
    Sun L, Cui M, Wang Z, Feng X, Mao J, Chen P, Kangtao M, Chen F, Zhou C (2007) Mesenchymal stem cells modified with angiopoietin-1 improve remodeling in a rat model of acute myocardial infarction. Biochem Biophys res Commun 357:779–784PubMedCrossRefGoogle Scholar
  164. 164.
    Anderlini P, Donato M, Chan KW, Huh YO, Gee AP, Lauppe MJ, Champlin RE, Korbling M (1999) Allogeneic blood progenitor cell collection in normal donors after mobilization with filgrastim: the M.D. Anderson Cancer Center experience. Transfusion 39:555–560PubMedCrossRefGoogle Scholar
  165. 165.
    Flomenberg N, DiPersio J, Calandra G (2005) Role of CXCR4 chemokine receptor blockade using AMD3100 for mobilization of autologous hematopoietic progenitor cells. Acta Haematol 114:198–205PubMedCrossRefGoogle Scholar
  166. 166.
    Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversam P (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A 98:10344–10349PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Minatoguchi S, Takemura G, Chen XH, Wang N, Uno Y, Koda M, Arai M, Misao Y, Lu C, Suzuki K, Goto K, Komada A, Takahashi T, Kosai K, Fujiwara T, Fujiwara H (2004) Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment. Circulation 109:2572–2580PubMedCrossRefGoogle Scholar
  168. 168.
    Werneck-de-Castro JP, Costa-e-Sousa RH, de Oliveira PF, Pinho-Ribeiro V, Mello DB, Pecanha R, Mattos E, Olivares EL, Maia AC, Mill JG, Goldenberg RC, Campos-de-Carvalho AC (2006) G-CSF does not improve systolic function in a rat model of acute myocardial infarction. Basic Res Cardiol 101:494–501PubMedCrossRefGoogle Scholar
  169. 169.
    Harada M, Qin Y, Takano H, Minamino T, Zou Y, Toko H, Ohtsuka M, Matsuura K, Sano M, Nishi J, Iwanaga K, Akazawa H, Kunieda T, Zhu W, Hasegawa H, Kunisada K, Nagai T, Nakaya H, Yamauchi-Takihara K, Komuro I (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 11:305–311PubMedCrossRefGoogle Scholar
  170. 170.
    Deindl E, Zaruba MM, Brunner S, Huber B, Mehl U, Assmann G, Hoefer IE, Mueller-Hoecker J, Franz WM (2006) G-CSF administration after myocardial infarction in mice attenuates late ischaemic cardiomyopathy by enhanced arteriogenesis. FASEB j 20:956–958PubMedCrossRefGoogle Scholar
  171. 171.
    Zhao Q, Sun C, Xu X, Zhou J, Wu Y, Tian Y, Ma A, Liu Z (2013) Early use of granulocyte colony stimulating factor improves survival in a rabbit model of chronic myocardial ischemia. J Cardiol 61:87–94PubMedCrossRefGoogle Scholar
  172. 172.
    Kastrup J, Ripa RS, Wang Y, Jorgensen E (2006) Myocardial regeneration induced by granulocyte-colony stimulating factor mobilization of stem cells in patients with acute or chronic ischaemic heart disease: a non-invasive alternative for clinical stem cell therapy. Eur Heart J 27:2748–2754PubMedCrossRefGoogle Scholar
  173. 173.
    Engelmann MG, Theiss HD, Theiss C, Huber A, Wintersperger BJ, Werle-Ruedinger AE, Schoenberg SO, Steinbeck G, Franz WM (2008) G-CSF in patients suffering from late revascularized ST elevation myocardial infarction: analysis on the timing of G-CSF administration. Exp Hematol 36:703–739PubMedCrossRefGoogle Scholar
  174. 174.
    Overgaard M, Ripa RS, Wang Y, Jørgensen E, Kastrup J (2010) Timing of granulocyte-colony stimulating factor treatment after acute myocardial infarction and recovery of left ventricular function: results from the STEMMI trial. Int J Cardiol 140:351–355PubMedCrossRefGoogle Scholar
  175. 175.
    Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 88:9271–9276CrossRefGoogle Scholar
  176. 176.
    Cao Y, Ji WR, Qi P, Rosin A, Cao Y (1997) Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing. Biochem Biophys Res Commun 235:493–498PubMedCrossRefGoogle Scholar
  177. 177.
    Weindel K, Moringlane JR, Marme D, Weich HA (1994) Detection and quantification of vascular endothelial growth factor/ vascular permeability factor in brain tumour tissue and cyst fluid: the key to angiogenesis? Neurosurgery 35:439–448PubMedCrossRefGoogle Scholar
  178. 178.
    Takahashi A, Sasaki H, Kim SJ, Sk T, Kakizoe T, Tsukamoto T, Kumamoto Y, Sugimura T, Terada M (1994) Marked increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated angiogenesis. Cancer res 54:4233–4237PubMedGoogle Scholar
  179. 179.
    Roncal C, Buysschaert I, Chorianopoulos E, Georgiadou M, Meilhac O, Demol M, Michel JB, Vinckier S, Moons L, Carmeliet P (2008) Beneficial effects of prolonged systemic administration of PIGF on late outcome of post-ischaemic myocardial performance. J Pathol 216:236–244PubMedCrossRefGoogle Scholar
  180. 180.
    Humbel RE (1990) Insulin like growth factors I and II. Eur J Biochem 190:445–462PubMedCrossRefGoogle Scholar
  181. 181.
    Neff NT, Prevette D, Houenou LJ, Lewis ME, Glicksman MA, Yin QW, Oppenheim RW (1993) Insulin like growth factors: putative muscle derived trophic agents that promote motoneuron survival. J Neurobiol 24:1578–1588PubMedCrossRefGoogle Scholar
  182. 182.
    Grant MB, Mames RN, Fitzerald C, Ellis EA, Aboufriekha M, Guy J (1993) Insulin like growth factor I acts as an angiogenic agent in rabbit cornea and retina: comparative studies with basic fibroblast growth factor. Diabetologia 36:282–291PubMedCrossRefGoogle Scholar
  183. 183.
    Dobrucki LW, Tsutsumi Y, Kalinowski L, Dean J, Gavin M, Sen S, Mendizabal M, Sinusas AJ, Aikawa R (2010) Analysis of angiogenesis induced by local IGF-1 expression after myocardial infarction using microSPECT-CT imaging. J Mol Cell Cardiol 48(6):1071–1079PubMedCrossRefGoogle Scholar
  184. 184.
    Friberg L, Werner S, Eggertsen G, Ahnve S (2000) Growth hormone and insulin like growth factor-1 in acute myocardial infarction. Eur Heart J 21:1547–1554PubMedCrossRefGoogle Scholar
  185. 185.
    Battler A, Hasdai D, Oldber I, Ohad D, Di Segni E, Bor A, Varda Bloom N, Vered Z, Kornowski R, Lake M, Nass D, Savion N (1995) Exogenous insulin like growth factor II enhances post-infarction regional myocardial infarction in swine. Eur Heart J 16:1851–1859PubMedCrossRefGoogle Scholar
  186. 186.
    Frantz S, Hu K, Adamek A, Wolf J, Sallam A, Maier SK, Lonning S, Ling H, Ertl G, Bauersachs J (2008) Transforming growth factor-beta inhibition increases mortality and left ventricular dilatation after myocardial infarction. Basic Res Cardiol 103:485–492PubMedCrossRefGoogle Scholar
  187. 187.
    Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alital K (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 269:6271–6274PubMedGoogle Scholar
  188. 188.
    Yamamoto T, Bing RJ (2000) Nitric oxide donors. PSEBM 225:200–206CrossRefGoogle Scholar
  189. 189.
    Hariawala MD, Sellke FW (1997) Angiogenesis and the heart: therapeutic implications. J R Soc Med 90:1022–1028CrossRefGoogle Scholar
  190. 190.
    Morbidelli L, Chan CH, Douglas JG, Granger HJ, Ledda F, Ziche M (1996) Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Phys 270:H411–H415Google Scholar
  191. 191.
    Epstein SE, Kornowski R, Fuchs S, Dvorak HF (2001) Angiogenesis therapy: amidst hype, the neglected potential for serious side effects. Circulation 104:115–119PubMedCrossRefGoogle Scholar
  192. 192.
    Khan TA, Sellke FW, Laham RJ (2003) Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia. Gene Ther 10:285–291PubMedCrossRefGoogle Scholar
  193. 193.
    Kornowski R, Fuchs S, Leon MB, Epstein SE (2000) Delivery strategies to achieve therapeutic myocardial angiogenesis. Circulation 101:454–458PubMedCrossRefGoogle Scholar
  194. 194.
    Chen H, Peng P, Cheng L, Lin X, Chung SS, Li M (2010) Reconstitution of coronary vasculature in ischemic hearts by plant-derived angiogenic compounds. Int J Cardiol 156:148–155PubMedCrossRefGoogle Scholar
  195. 195.
    Moon EJ, Lee YM, Lee OH, Lee MJ, Lee SK, Chung MH, Park YI, Sung CK, Choi JS, Kim KW (1999) A novel angiogenic factor derived from Aloe vera gel: beta-sitosterol, a plant sterol. Angiogenesis 3:117–123PubMedCrossRefGoogle Scholar
  196. 196.
    Fukuda S, Kaga S, Zhan L, Bagchi D, Das DK, Bertelli A, Maulik N (2006) Resveratrol ameliorates myocardial damage by inducing vascular endothelial growth factor-angiogenesis and tyrosine kinase receptor Flk-1. Cell Biochem Biophys 44:43–49PubMedCrossRefGoogle Scholar
  197. 197.
    Sengupta S, Toh SA, Sellers LA, Skepper JN, Koolwijk P, Leung HW, Yeung HW, Wong RN, Sasisekharan R, Fan TP (2004) Modulating angiogenesis: the Yin and the Yang in ginseng. Circulation 110:1219–1225PubMedCrossRefGoogle Scholar
  198. 198.
    Trelles DR, Scimia MC, Bushway P, Tran D, Monosov A, Monosov E, Peterson K, Rentschler S, Cabrales P, Ruiz-Lozano P, Mercola M (2016) Notch-independent RBPJ controls angiogenesis in the adult heart. Nat Commun 7:12088. doi: 10.1038/ncomms12088 CrossRefGoogle Scholar
  199. 199.
    Singla DK (2016) Stem cells and exosomes in cardiac repair. Curr Opin Pharmacol 27:19–23PubMedCrossRefGoogle Scholar
  200. 200.
    Zhaofu L, Dongqing C (2016) Cardiac telocytes in regeneration of myocardium after myocardial infarction. Adv Exp med Biol 913:229–239PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Hemalatha Thiagarajan
    • 1
  • UmaMaheswari Thiyagamoorthy
    • 2
  • Iswariya Shanmugham
    • 1
  • Gunadharini Dharmalingam Nandagopal
    • 1
  • Anbukkarasi Kaliyaperumal
    • 3
  1. 1.Department of Biological MaterialsCSIR - Central Leather Research InstituteChennaiIndia
  2. 2.Department of Food Science and Nutrition, Home Science College and Research InstituteTamil Nadu Agricultural UniversityMaduraiIndia
  3. 3.Department of Agricultural MicrobiologyRVS Agriculture CollegeThanjavurIndia

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