Skip to main content

Advertisement

SpringerLink
Log in

Approaches to therapeutic angiogenesis for ischemic heart disease

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Ischemic heart disease (IHD) is caused by the narrowing of arteries that work to provide blood, nutrients, and oxygen to the myocardial tissue. The worldwide epidemic of IHD urgently requires innovative treatments despite the significant advances in medical, interventional, and surgical therapies for this disease. Angiogenesis is a physiological and pathophysiological process that initiates vascular growth from pre-existing blood vessels in response to a lack of oxygen. This process occurs naturally over time and has encouraged researchers and clinicians to investigate the outcomes of accelerating or enhancing this angiogenic response as an alternative IHD therapy. Therapeutic angiogenesis has been shown to revascularize ischemic heart tissue, reduce the progression of tissue infarction, and evade the need for invasive surgical procedures or tissue/organ transplants. Several approaches, including the use of proteins, genes, stem/progenitor cells, and various combinations, have been employed to promote angiogenesis. While clinical trials for these approaches are ongoing, microvesicles and exosomes have recently been investigated as a cell-free approach to stimulate angiogenesis and may circumvent limitations of using viable cells. This review summarizes the approaches to accomplish therapeutic angiogenesis for IHD by highlighting the advances and challenges that addresses the applicability of a potential pro-angiogenic medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AMI:

Acute myocardial infarction

ASC:

Adipose-derived stem cell

BM:

Bone marrow

CABG:

Coronary artery bypass grafting

CCSAC:

Canadian Cardiovascular Society Angina Classification

EC:

Endothelial cells

EDV:

End diastolic volume

EMT:

Epithelial to mesenchymal transition

FGF:

Fibroblast growth factor

EPC:

Endothelial progenitor cell

EV:

Extracellular vesicles

HIF-1α:

Hypoxia inducible factor-1α

IC:

Intracoronary infusion

IHD:

Schemic heart disease

IM:

Intramyocardial injection

IPSC:

Induced pluripotent stem cell

IVPC:

Induced vascular progenitor cell

LVEF:

Left ventricle ejection fraction

LVESV:

Left ventricle end systolic volume

MSC:

Mesenchymal stem cells

MV:

Microvesicle

PCI:

Percutaneous injection

PlGF:

Placental-derived growth factor

PDGF:

Platelet-derived growth factor

SDF1:

Stromal cell-derived factor 1

TV:

tail vein

VEGF:

Vascular endothelial growth factor

References

  1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C et al (2017) Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135:e146–e603

    PubMed  PubMed Central  Google Scholar 

  2. Dragneva G, Korpisalo P, Yla-Herttuala S (2013) Promoting blood vessel growth in ischemic diseases: challenges in translating preclinical potential into clinical success. Dis Model Mech 6:312–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang X-L, Zhu Q-Q, Yang J-J, Chen Y-H, Li Y, Zhu S-H, Xie J, Wang L, Kang L-N, Xu B (2017) Percutaneous intervention versus coronary artery bypass graft surgery in left main coronary artery stenosis: a systematic review and meta-analysis. BMC Med 15:84

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rodriguez AE, Pavlovsky H, Del Pozo JF (2016) Understanding the outcome of randomized trials with drug-eluting stents and coronary artery bypass graft in patients with multivessel disease: a review of a 25-year journey. Clin Med Insights Cardiol 10:195–199

    Article  PubMed  PubMed Central  Google Scholar 

  5. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Stahle E, Feldman TE, van den Brand M, Bass EJ et al (2009) Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 360:961–972

    Article  CAS  PubMed  Google Scholar 

  6. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934

    CAS  PubMed  Google Scholar 

  7. Shimamura M, Nakagami H, Taniyama Y, Morishita R (2014) Gene therapy for peripheral arterial disease. Expert Opin Biol Ther 14:1175–1184

    Article  CAS  PubMed  Google Scholar 

  8. Gibson CM, Ryan K, Sparano A, Moynihan JL, Rizzo M, Kelley M, Marble SJ, Laham R, Simons M, McClusky TR et al (1999) Angiographic methods to assess human coronary angiogenesis. Am Heart J 137:169–179

    Article  CAS  PubMed  Google Scholar 

  9. Ribatti D, Conconi MT, Nussdorfer GG (2007) Nonclassic endogenous novel regulators of angiogenesis. Pharmacol Rev 59:185–205

    Article  CAS  PubMed  Google Scholar 

  10. Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507

    Article  CAS  PubMed  Google Scholar 

  11. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    Article  CAS  PubMed  Google Scholar 

  12. Persson AB, Buschmann IR (2011) Vascular growth in health and disease. Front Mol Neurosci 4:14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Meier P, Seiler C (2014) The coronary collateral circulation—past, present and future. Curr Cardiol Rev 10:1

    Article  PubMed  PubMed Central  Google Scholar 

  14. Patel-Hett S, D’Amore PA (2011) Signal transduction in vasculogenesis and developmental angiogenesis. Int J Dev Biol 55:353–363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Balaji S, King A, Crombleholme TM, Keswani SG (2013) The role of endothelial progenitor cells in postnatal vasculogenesis: implications for therapeutic neovascularization and wound healing. Adv Wound Care (New Rochelle) 2:283–295

    Article  Google Scholar 

  16. Rissanen TT, Yla-Herttuala S (2007) Current status of cardiovascular gene therapy. Mol Ther 15:1233–1247

    Article  CAS  PubMed  Google Scholar 

  17. Zhu H, Jiang X, Li X, Hu M, Wan W, Wen Y, He Y, Zheng X (2016) Intramyocardial delivery of VEGF165 via a novel biodegradable hydrogel induces angiogenesis and improves cardiac function after rat myocardial infarction. Heart Vessel 31:963–975

    Article  Google Scholar 

  18. Hedman M, Hartikainen J, Syvanne M, Stjernvall J, Hedman A, Kivela A, Vanninen E, Mussalo H, Kauppila E, Simula S et al (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 107:2677–2683

    Article  CAS  PubMed  Google Scholar 

  19. Moimas S, Manasseri B, Cuccia G, Stagno d’Alcontres F, Geuna S, Pattarini L, Zentilin L, Giacca M, Colonna MR (2015) AAV vector encoding human VEGF165-transduced pectineus muscular flaps increase the formation of new tissue through induction of angiogenesis in an in vivo chamber for tissue engineering: a technique to enhance tissue and vessels in microsurgically engineered tissue. J Tissue Eng 6:2041731415611717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Stewart DJ, Hilton JD, Arnold JMO, Gregoire J, Rivard A, Archer SL, Charbonneau F, Cohen E, Curtis M, Buller CE et al (2006) Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF121 (AdVEGF121) versus maximum medical treatment. Gene Ther 13:1503–1511

    Article  CAS  PubMed  Google Scholar 

  21. Ripa RS, Wang Y, Jorgensen E, Johnsen HE, Hesse B, Kastrup J (2006) 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 27:1785–1792

    Article  CAS  PubMed  Google Scholar 

  22. Grines CL, Watkins MW, Mahmarian JJ, Iskandrian AE, Rade JJ, Marrott P, Pratt C, Kleiman N (2003) 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 42:1339–1347

    Article  CAS  PubMed  Google Scholar 

  23. Bellu AR, Rotz MG, Bouis D, Mulder NH, Dam W, Vv W, Koolwijk P, Quax PHA, Haisma HJ, Hosper GAP (2004) 153. VEGF associated with TP to refine angiogenesis in gene therapy. Mol Ther 9:S58–S59

    Google Scholar 

  24. Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E, Leboulch P, Cao Y (2003) Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 9:604–613

    Article  CAS  PubMed  Google Scholar 

  25. Kano MR, Morishita Y, Iwata C, Iwasaka S, Watabe T, Ouchi Y, Miyazono K, Miyazawa K (2005) VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. J Cell Sci 118:3759–3768

    Article  CAS  PubMed  Google Scholar 

  26. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B et al (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840

    Article  CAS  PubMed  Google Scholar 

  27. Bai Y, Leng Y, Yin G, Pu X, Huang Z, Liao X, Chen X, Yao Y (2014) Effects of combinations of BMP-2 with FGF-2 and/or VEGF on HUVECs angiogenesis in vitro and CAM angiogenesis in vivo. Cell Tissue Res 356:109–121

    Article  CAS  PubMed  Google Scholar 

  28. Boyle AJ, McNiece IK, Hare JM (2010) Mesenchymal stem cell therapy for cardiac repair. Methods Mol Biol 660:65–84

    Article  CAS  PubMed  Google Scholar 

  29. Lee EJ, Park HW, Jeon HJ, Kim HS, Chang MS (2013) Potentiated therapeutic angiogenesis by primed human mesenchymal stem cells in a mouse model of hindlimb ischemia. Regen Med 8:283–293

    Article  CAS  PubMed  Google Scholar 

  30. Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E (2014) Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev CD007888. https://doi.org/10.1002/14651858.CD007888.pub2

  31. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964

    Article  CAS  PubMed  Google Scholar 

  32. Li Y, Tian S, Lei I, Liu L, Ma P, Wang Z (2017) Transplantation of multipotent Isl1+ cardiac progenitor cells preserves infarcted heart function in mice. Am J Transl Res 9:1530–1542

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhao L, Johnson T, Liu D (2017) Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. Stem Cell Res Ther 8:125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fadini GP, Losordo D, Dimmeler S (2012) Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 110:624–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Medina RJ, Barber CL, Sabatier F, Dignat-George F, Melero-Martin JM, Khosrotehrani K, Ohneda O, Randi AM, Chan JKY, Yamaguchi T et al (2017) Endothelial progenitors: a consensus statement on nomenclature. Stem Cells Transl Med 6:1316–1320

    Article  PubMed  PubMed Central  Google Scholar 

  36. Miettinen JA, Salonen RJ, Niemela M, Kervinen K, Saily M, Koistinen P, Savolainen ER, Ukkonen H, Pietila M, Airaksinen KE et al (2010) Effects of intracoronary infusion of bone marrow-derived stem cells on pulmonary artery pressure and diastolic function after myocardial infarction. Int J Cardiol 145:631–633

    Article  PubMed  Google Scholar 

  37. Pokushalov E, Romanov A, Chernyavsky A, Larionov P, Terekhov I, Artyomenko S, Poveshenko O, Kliver E, Shirokova N, Karaskov A et al (2010) Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: a randomized study. J Cardiovasc Transl Res 3:160–168

    Article  PubMed  Google Scholar 

  38. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW et al (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221

    Article  CAS  PubMed  Google Scholar 

  39. Ahmadi H, Baharvand H, Ashtiani SK, Soleimani M, Sadeghian H, Ardekani JM, Mehrjerdi NZ, Kouhkan A, Namiri M, Madani-Civi M et al (2007) Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction. Curr Neurovasc Res 4:153–160

    Article  PubMed  Google Scholar 

  40. Nasseri BA, Ebell W, Dandel M, Kukucka M, Gebker R, Doltra A, Knosalla C, Choi YH, Hetzer R, Stamm C (2014) Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur Heart J 35:1263–1274

    Article  CAS  PubMed  Google Scholar 

  41. Povsic TJ, Junge C, Nada A, Schatz RA, Harrington RA, Davidson CJ, Fortuin FD, Kereiakes DJ, Mendelsohn FO, Sherman W et al (2013) A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study. Am Heart J 165:854–861 e852

    Article  CAS  PubMed  Google Scholar 

  42. Wojakowski W, Pyrlik A, Krol M, Buszman P, Ochala A, Milewski K, Smolka G, Kawecki D, Rudnik A, Pawlowski T et al (2013) Circulating endothelial progenitor cells are inversely correlated with in-stent restenosis in patients with non-ST-segment elevation acute coronary syndromes treated with EPC-capture stents (JACK-EPC trial). Minerva Cardioangiol 61:301–311

    CAS  PubMed  Google Scholar 

  43. Aguado BA, Mulyasasmita W, Su J, Lampe KJ, Heilshorn SC (2012) Improving viability of stem cells during syringe needle flow through the design of hydrogel cell carriers. Tissue Eng A 18:806–815

    Article  CAS  Google Scholar 

  44. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B (2012) Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 126:551–568

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lee JW, Lee SH, Youn YJ, Ahn MS, Kim JY, Yoo BS, Yoon J, Kwon W, Hong IS, Lee K et al (2014) A randomized, open-label, multicenter trial for the safety and efficacy of adult mesenchymal stem cells after acute myocardial infarction. J Korean Med Sci 29:23–31

    Article  PubMed  Google Scholar 

  46. Hou L, Kim JJ, Woo YJ, Huang NF (2016) Stem cell-based therapies to promote angiogenesis in ischemic cardiovascular disease. Am J Physiol Heart Circ Physiol 310:H455

    Article  PubMed  Google Scholar 

  47. Liao YY, Chen ZY, Wang YX, Lin Y, Yang F, Zhou QL (2014) New progress in angiogenesis therapy of cardiovascular disease by ultrasound targeted microbubble destruction. Biomed Res Int 2014:872984

    PubMed  PubMed Central  Google Scholar 

  48. Lee S, Valmikinathan CM, Byun J, Kim S, Lee G, Mokarram N, Pai SB, Um E, Bellamkonda RV, Yoon YS (2015) Enhanced therapeutic neovascularization by CD31-expressing cells and embryonic stem cell-derived endothelial cells engineered with chitosan hydrogel containing VEGF-releasing microtubes. Biomaterials 63:158–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hirschi KK, Li S, Roy K (2014) Induced pluripotent stem cells for regenerative medicine. Annu Rev Biomed Eng 16:277–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yin L, Ohanyan V, Fen Pung Y, DeLucia A, Bailey E, Enrick M, Stevanov K, Kolz CL, Guarini G, Chilian WM (2012) Induction of vascular progenitor cells from endothelial cells stimulates coronary collateral growth. Circ Res 110:241–252

    Article  CAS  PubMed  Google Scholar 

  51. Pons J, Huang Y, Takagawa J, Arakawa-Hoyt J, Ye J, Grossman W, Kan YW, Su H (2009) Combining angiogenic gene and stem cell therapies for myocardial infarction. J Gene Med 11:743–753

    Article  CAS  PubMed  Google Scholar 

  52. Huang B, Qian J, Ma J, Huang Z, Shen Y, Chen X, Sun A, Ge J, Chen H (2014) Myocardial transfection of hypoxia-inducible factor-1a and co-transplantation of mesenchymal stem cells enhance cardiac repair in rats with experimental myocardial infarction. Stem Cell Res Ther 5:22–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Duan HF, Wu CT, Wu DL, Lu Y, Liu HJ, Ha XQ, Zhang QW, Wang H, Jia XX, Wang LS (2003) Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Mol Ther 8:467–474

    Article  CAS  PubMed  Google Scholar 

  54. Shao H, Tan Y, Eton D, Yang Z, Uberti MG, Li S, Schulick A, Yu H (2008) Statin and stromal cell-derived factor-1 additively promote angiogenesis by enhancement of progenitor cells incorporation into new vessels. Stem Cells 26:1376–1384

    Article  CAS  PubMed  Google Scholar 

  55. Bandara N, Gurusinghe S, Chen H, Chen S, Wang L-x, Lim SY, Strappe P (2016) Minicircle DNA-mediated endothelial nitric oxide synthase gene transfer enhances angiogenic responses of bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther 7:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jung J-H, Fu X, Yang PC (2017) Exosomes generated from iPSC-derivatives. New direction for stem cell therapy in human heart diseases. Circ Res 120:407–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV, Mathivanan S, Quesenberry P et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3:26913

    Article  PubMed  Google Scholar 

  58. Lawson C, Vicencio JM, Yellon DM, Davidson SM (2016) Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol 228:R57–R71

    Article  PubMed  Google Scholar 

  59. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L (2010) Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 78:838–848

    Article  CAS  PubMed  Google Scholar 

  60. Zhu H, Fan GC (2011) Extracellular/circulating microRNAs and their potential role in cardiovascular disease. Am J Cardiovasc Dis 1:138–149

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Harp D, Driss A, Mehrabi S, Chowdhury I, Xu W, Liu D, Garcia-Barrio M, Taylor RN, Gold B, Jefferson S et al (2016) Exosomes derived from endometriotic stromal cells have enhanced angiogenic effects in vitro. Cell Tissue Res 365:187–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vickers KC, Remaley AT (2012) Lipid-based carriers of microRNAs and intercellular communication. Curr Opin Lipidol 23:91–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593

    Article  CAS  PubMed  Google Scholar 

  64. Li X, Chen C, Wei L, Li Q, Niu X, Xu Y, Wang Y, Zhao J (2016) Exosomes derived from endothelial progenitor cells attenuate vascular repair and accelerate reendothelialization by enhancing endothelial function. Cytotherapy 18:253–262

    Article  CAS  PubMed  Google Scholar 

  65. Gray WD, French KM, Ghosh-Choudhary S, Maxwell JT, Brown ME, Platt MO, Searles CD, Davis ME (2015) Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 116:255–263

    Article  CAS  PubMed  Google Scholar 

  66. Kang T, Jones TM, Naddell C, Bacanamwo M, Calvert JW, Thompson WE, Bond VC, Chen YE, Liu D (2016) Adipose-derived stem cells induce angiogenesis via microvesicle transport of miRNA-31. Stem Cells Transl Med 5:440–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Foglio E, Puddighinu G, Fasanaro P, D’Arcangelo D, Perrone GA, Mocini D, Campanella C, Coppola L, Logozzi M, Azzarito T et al (2015) Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis. Int J Cardiol 197:333–347

    Article  PubMed  Google Scholar 

  68. Beltrami C, Besnier M, Shantikumar S, Shearn AIU, Rajakaruna C, Laftah A, Sessa F, Spinetti G, Petretto E, Angelini GD et al (2017) Human pericardial fluid contains exosomes enriched with cardiovascular-expressed microRNAs and promotes therapeutic angiogenesis. Mol Ther 25:679–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Atienzar-Aroca S, Flores-Bellver M, Serrano-Heras G, Martinez-Gil N, Barcia JM, Aparicio S, Perez-Cremades D, Garcia-Verdugo JM, Diaz-Llopis M, Romero FJ et al (2016) Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells. J Cell Mol Med 20:1457–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kang K, Ma R, Cai W, Huang W, Paul C, Liang J, Wang Y, Zhao T, Kim HW, Xu M et al (2015) Exosomes secreted from CXCR4 overexpressing mesenchymal stem cells promote cardioprotection via Akt signaling pathway following myocardial infarction. Stem Cells Int 2015:659890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ma J, Zhao Y, Sun L, Sun X, Zhao X, Sun X, Qian H, Xu W, Zhu W (2017) Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cells Transl Med 6:51–59

    Article  CAS  PubMed  Google Scholar 

  72. Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H (2014) Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 92:387–397

    Article  CAS  Google Scholar 

  73. Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z (2015) Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem 37:2415–2424

    Article  CAS  PubMed  Google Scholar 

  74. Zhang Z, Yang J, Yan W, Li Y, Shen Z, Asahara T (2016) Pretreatment of cardiac stem cells with exosomes derived from mesenchymal stem cells enhances myocardial repair. J Am Heart Assoc 5:e002856

    PubMed  PubMed Central  Google Scholar 

  75. Wang N, Chen C, Yang D, Liao Q, Luo H, Wang X, Zhou F, Yang X, Yang J, Zeng C et al (2017) Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis. Biochim Biophys Acta (BBA) - Mol Basis Dis 1863:2085–2092

    Article  CAS  Google Scholar 

  76. Izarra A, Moscoso I, Levent E, Cañón S, Cerrada I, Díez-Juan A, Blanca V, Núñez-Gil I-J, Valiente I, Ruíz-Sauri A et al (2014) miR-133a enhances the protective capacity of cardiac progenitors cells after myocardial infarction. Stem Cell Rep 3:1029–1042

    Article  CAS  Google Scholar 

  77. Barile L, Lionetti V, Cervio E, Matteucci M, Gherghiceanu M, Popescu LM, Torre T, Siclari F, Moccetti T, Vassalli G (2014) Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 103:530–541

    Article  CAS  PubMed  Google Scholar 

  78. Tseliou E, Fouad J, Reich H, Slipczuk L, de Couto G, Aminzadeh M, Middleton R, Valle J, Weixin L, Marbán E (2015) Exosomes from cardiac stem cells amplify their own bioactivity by converting fibroblasts to therapeutic cells. J Am Coll Cardiol 66:599–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Agarwal U, George A, Bhutani S, Ghosh-Choudhary S, Maxwell JT, Brown ME, Mehta Y, Platt MO, Liang Y, Sahoo S et al (2017) Experimental, systems, and computational approaches to understanding the microRNA-mediated reparative potential of cardiac progenitor cell-derived exosomes from pediatric patients. Circ Res 120:701–712

    Article  CAS  PubMed  Google Scholar 

  80. Gallet R, Dawkins J, Valle J, Simsolo E, de Couto G, Middleton R, Tseliou E, Luthringer D, Kreke M, Smith RR et al (2017) Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J 38:201–211

    CAS  PubMed  Google Scholar 

  81. Khan M, Nickoloff E, Abramova T, Johnson J, Verma SK, Krishnamurthy P, Mackie AR, Vaughan E, Garikipati VNS, Benedict C et al (2015) Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res 117:52–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kervadec A, Bellamy V, El Harane N, Arakélian L, Vanneaux V, Cacciapuoti I, Nemetalla H, Périer M-C, Toeg HD, Richart A et al (2016) Cardiovascular progenitor–derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J Heart Lung Transplant 35:795–807

    Article  PubMed  Google Scholar 

  83. Xiong Y, Zhang Y, Mahmood A, Chopp M (2015) Investigational agents for treatment of traumatic brain injury. Expert Opin Investig Drugs 24:743–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sato YT, Umezaki K, Sawada S, Sa M, Sasaki Y, Harada N, Shiku H, Akiyoshi K (2016) Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep 6:21933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kanada M, Bachmann MH, Hardy JW, Frimannson DO, Bronsart L, Wang A, Sylvester MD, Schmidt TL, Kaspar RL, Butte MJ et al (2015) Differential fates of biomolecules delivered to target cells via extracellular vesicles. Proc Natl Acad Sci 112:E1433–E1442

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M (2014) A comprehensive overview of exosomes as drug delivery vehicles—endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta 1846:75–87

    CAS  PubMed  Google Scholar 

  87. Xitong D, Xiaorong Z (2016) Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases. Gene 575:377–384

    Article  CAS  PubMed  Google Scholar 

  88. El-Andaloussi S, Lee Y, Lakhal-Littleton S, Li J, Seow Y, Gardiner C, Alvarez-Erviti L, Sargent IL, Wood MJA (2012) Exosome-mediated delivery of siRNA in vitro and in vivo. Nat Protoc 7:2112–2126

    Article  CAS  PubMed  Google Scholar 

  89. Won Kim H, Haider HK, Jiang S, Ashraf M (2009) Ischemic preconditioning augments survival of stem cells via miR-210 expression by targeting caspase-8-associated protein 2. J Biol Chem 284:33161–33168

    Article  CAS  PubMed Central  Google Scholar 

  90. Leroux L, Descamps B, Tojais NF, Seguy B, Oses P, Moreau C, Daret D, Ivanovic Z, Boiron JM, Lamaziere JM et al (2010) Hypoxia preconditioned mesenchymal stem cells improve vascular and skeletal muscle fiber regeneration after ischemia through a Wnt4-dependent pathway. Mol Ther 18:1545–1552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kucharzewska P, Belting M (2013) Emerging roles of extracellular vesicles in the adaptive response of tumour cells to microenvironmental stress. J Extracell Vesicles 2:10

    Article  PubMed Central  Google Scholar 

  92. Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringner M, Morgelin M, Bourseau-Guilmain E, Bengzon J, Belting M (2013) Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A 110:7312–7317

    Article  PubMed  PubMed Central  Google Scholar 

  93. Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, Nolte-‘t Hoen EN, Piper MG, Sivaraman S, Skog J et al (2013) Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2. https://doi.org/10.3402/jev.v2i0.20360

  94. Escudier B, Dorval T, Chaput N, Andre F, Caby MP, Novault S, Flament C, Leboulaire C, Borg C, Amigorena S et al (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med 3:10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Conlan RS, Pisano S, Oliveira MI, Ferrari M, Mendes Pinto I (2017) Exosomes as reconfigurable therapeutic systems. Trends Mol Med 23:636–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Choo ABH, Padmanabhan J, Lee CN, de Kleijn DPV, Lim SK (2011) Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med 9:47–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Radenkovic D, Arjun S, Poma A, Nyberg S, Battaglia B, Yellon DM, Davidson S (2016) 162 polymersomes functionalized with hsp70 – novel, synthetic cardioprotective nanovesicles. Heart 102:A115–A115

    Article  Google Scholar 

  98. Zhu K, Li J, Wang Y, Lai H, Wang C (2016) Nanoparticles-assisted stem cell therapy for ischemic heart disease. Stem Cells Int 2016:1384658

    PubMed  Google Scholar 

  99. Chu H, Wang Y (2012) Therapeutic angiogenesis: controlled delivery of angiogenic factors. Ther Deliv 3:693–714

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Morehouse School of Medicine, Cardiovascular Research Institute, 720 Westview Drive SW, Atlanta, GA, 30310, USA

    Takerra Johnson, Lina Zhao, Herman Taylor & Dong Liu

  2. Department of Biochemistry, Spelman College, 350 Spelman Lane, Atlanta, GA, 30314, USA

    Gygeria Manuel

Authors
  1. Takerra Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lina Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gygeria Manuel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Herman Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Johnson, T., Zhao, L., Manuel, G. et al. Approaches to therapeutic angiogenesis for ischemic heart disease. J Mol Med 97, 141–151 (2019). https://doi.org/10.1007/s00109-018-1729-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-018-1729-3

Keywords

Search

Navigation