Functional Role of Cardiovascular Exosomes in Myocardial Injury and Atherosclerosis

  • Maarten Vanhaverbeke
  • Diane Gal
  • Paul HolvoetEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 998)


Extracellular vesicles are now widely recognized as key players in the prevention, repair or progression of cardiovascular disease. Here we first focus on the functional roles of extracellular vesicles in the cross-talk between cardiomyocytes and endothelial cells, important for maintaining normal development and function of the heart. Second, we discuss the role of extracellular vesicles secreted by embryonic and non-embryonic stem cells in repairing cardiomyocyte function and in restoring angiogenic potential after myocardial ischemia-reperfusion injury. Third, we focus on the role of extracellular vesicles in Endothelial to Mesenchymal Transition (EndMT), leading to conversion of endothelial cells to fibroblasts, secretion of extracellular proteins collagen and fibronectin, and fibrosis. Finally, we discuss the role of extracellular vesicles secreted under stress by endothelial cells, macrophages and vascular smooth muscle cells in atherosclerosis. On aggregate, the reviewed preclinical studies present evidence that extracellular vesicles secreted by cardiomyocytes, fibroblasts, endothelial cells, immune-system-related cells, vascular smooth muscle cells and stem cells play an important role in the pathogenesis of cardiovascular disease. However, further studies are needed to gain better insight into the mechanisms used to select specific content to transfer to specific target cells, and to induce or repress signaling pathways in their target cells.


Exosomes Cardiac Vascular tissue Stem cells miRs 


  1. 1.
    de Almeida DC, Ferreira MRP, Franzen J, Weidner CI, Frobel J, Zenke M, Costa IG, Wagner W (2016) Epigenetic classification of human mesenchymal stromal cells. Stem Cell Rep 6:168–175CrossRefGoogle Scholar
  2. 2.
    Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, Montgomery EN, Mellema MS, Bardini RL, Contreras Z, Hoon M, Bauer G, Fink KD, Fury B, Hendrix KJ, Chedin F, EL-Andaloussi S, Hwang B, Mulligan MS, Lehtiö J, Nolta JA (2016) Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-KappaB signaling: MSC exosomes induce angiogenesis via NFkB pathway. Stem Cells 34:601–613CrossRefPubMedGoogle Scholar
  3. 3.
    Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor ENE, Timmers L, van Rijen HV, Doevendans PA, Pasterkamp G, Lim SK, de Kleijn DP (2013) Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res 10:301–312CrossRefPubMedGoogle Scholar
  4. 4.
    Banerjee I, Fuseler JW, Price RL, Borg TK, Baudino TA (2007) Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse. Am J Phys Heart Circ Phys 293:H1883–H1891Google Scholar
  5. 5.
    Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A, Just A, Remke J, Zimmer K, Zeug A, Ponimaskin E, Schmiedl A, Yin X, Mayr M, Halder R, Fischer A, Engelhardt S, Wei Y, Schober A, Fiedler J, Thum T (2014) Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Investig 124:2136–2146CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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 92:387–397CrossRefPubMedGoogle Scholar
  7. 7.
    Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang M-L, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MVG, Høydal M, Autore C, Russo MA, Dorn GW, Ellingsen O, Ruiz-Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G (2007) MicroRNA-133 controls cardiac hypertrophy. Nat Med 13:613–618CrossRefPubMedGoogle Scholar
  8. 8.
    Chen P-Y, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, Tellides G, Schwartz MA, Simons M (2015) Endothelial-to-mesenchymal transition drives atherosclerosis progression. J Clin Investig 125:4514–4528CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Comelli L, Rocchiccioli S, Smirni S, Salvetti A, Signore G, Citti L, Trivella MG, Cecchettini A (2014) Characterization of secreted vesicles from vascular smooth muscle cells. Mol Biosyst 10:1146–1152CrossRefPubMedGoogle Scholar
  10. 10.
    Deng W, Feng X, Li X, Wang D, Sun L (2016) Hypoxia-inducible factor 1 in autoimmune diseases. Cell Immunol 303:7–15CrossRefPubMedGoogle Scholar
  11. 11.
    Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156CrossRefPubMedGoogle Scholar
  12. 12.
    Feng B, Cao Y, Chen S, Chu X, Chu Y, Chakrabarti S (2016) miR-200b mediates endothelial-to-mesenchymal transition in diabetic cardiomyopathy. Diabetes 65:768–779CrossRefPubMedGoogle Scholar
  13. 13.
    Giricz Z, Varga ZV, Baranyai T, Sipos P, Pálóczi K, Kittel Á, Buzás EI, Ferdinandy P (2014) Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J Mol Cell Cardiol 68:75–78CrossRefPubMedGoogle Scholar
  14. 14.
    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 116:255–263CrossRefPubMedGoogle Scholar
  15. 15.
    Gupta S, Knowlton AA (2007) HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Phys Heart Circ Phys 292:H3052–H3056Google Scholar
  16. 16.
    Henning RJ (2011) Stem cells in cardiac repair. Futur Cardiol 7:99–117CrossRefGoogle Scholar
  17. 17.
    Holvoet P, Vanhaverbeke M, Bloch K, Baatsen P, Sinnaeve P, Janssens S (2016) Low MT-CO1 in monocytes and microvesicles is associated with outcome in patients with coronary artery disease. J Am Heart Assoc 5:e004207CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hu G, Li Q, Niu X, Hu B, Liu J, Zhou S, Guo S, Lang H, Zhang C, Wang Y, Deng Z (2015) Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Res Ther 6:10CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Huber HJ, Holvoet P (2015) Exosomes: emerging roles in communication between blood cells and vascular tissues during atherosclerosis. Curr Opin Lipidol 26:412–419CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hulsmans M, Holvoet P (2013) MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res 100:7–18CrossRefPubMedGoogle Scholar
  21. 21.
    Kanwar SS, Dunlay CJ, Simeone DM, Nagrath S (2014) Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes. Lab Chip 14:1891CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kapustin AN, Chatrou MLL, Drozdov I, Zheng Y, Davidson SM, Soong D, Furmanik M, Sanchis P, De Rosales RTM, Alvarez-Hernandez D, Shroff R, Yin X, Muller K, Skepper JN, Mayr M, Reutelingsperger CP, Chester A, Bertazzo S, Schurgers LJ, Shanahan CM (2015) Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res 116:1312–1323CrossRefPubMedGoogle Scholar
  23. 23.
    Kervadec A, Bellamy V, El Harane N, Arakélian L, Vanneaux V, Cacciapuoti I, Nemetalla H, Périer M-C, Toeg HD, Richart A, Lemitre M, Yin M, Loyer X, Larghero J, Hagège A, Ruel M, Boulanger CM, Silvestre J-S, Menasché P, Renault NKE (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 35:795–807CrossRefPubMedGoogle Scholar
  24. 24.
    Khan M, Nickoloff E, Abramova T, Johnson J, Verma SK, Krishnamurthy P, Mackie AR, Vaughan E, Garikipati VNS, Benedict C, Ramirez V, Lambers E, Ito A, Gao E, Misener S, Luongo T, Elrod J, Qin G, Houser SR, Koch WJ, Kishore R (2015) Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res 117:52–64CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V (2012) Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. Circulation 125:1795–1808CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Kinoshita M, Watanabe S, Baba O, Kojima Y, Shizuta S, Imai M, Tamura T, Kita T, Kimura T (2011) Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet 4:446–454CrossRefPubMedGoogle Scholar
  27. 27.
    Liang X, Zhang L, Wang S, Han Q, Zhao RC (2016) Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci 129:2182–2189CrossRefPubMedGoogle Scholar
  28. 28.
    Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G (2014) Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal 12:26CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lyu L, Wang H, Li B, Qin Q, Qi L, Nagarkatti M, Nagarkatti P, Janicki JS, Wang XL, Cui T (2015) A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes. J Mol Cell Cardiol 89:268–279CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mackie AR, Klyachko E, Thorne T, Schultz KM, Millay M, Ito A, Kamide CE, Liu T, Gupta R, Sahoo S, Misener S, Kishore R, Losordo DW (2012) Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction. Circ Res 111:312–321CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Markwald RR, Fitzharris TP, Manasek FJ (1977) Structural development of endocardial cushions. Am J Anat 148:85–119CrossRefPubMedGoogle Scholar
  32. 32.
    Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707–721CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Niu C, Wang X, Zhao M, Cai T, Liu P, Li J, Willard B, Zu L, Zhou E, Li Y, Pan B, Yang F, Zheng L (2016) Macrophage foam cell–derived extracellular vesicles promote vascular smooth muscle cell migration and adhesion. J Am Heart Assoc 5:e004099CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Peterson MF, Otoc N, Sethi JK, Gupta A, Antes TJ (2015) Integrated systems for exosome investigation. Methods 87:31–45CrossRefPubMedGoogle Scholar
  35. 35.
    Safari S, Malekvandfard F, Babashah S, Alizadehasl A, Sadeghizadeh M, Motavaf M (2016) Mesenchymal stem cell-derived exosomes: a novel potential therapeutic avenue for cardiac regeneration. Cell Mol Biol (Noisy-le-grand) 62:66–73Google Scholar
  36. 36.
    Sahoo S, Klychko E, Thorne T, Misener S, Schultz KM, Millay M, Ito A, Liu T, Kamide C, Agrawal H, Perlman H, Qin G, Kishore R, Losordo DW (2011) Exosomes from human CD34+ stem cells mediate their proangiogenic paracrine activity. Circ Res 109:724–728CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Badiavas EV (2015) Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev 24:1635–1647CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, Blumenthal PD, Huggins GR, Gearhart JD (1998) Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A 95:13726–13731CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Singh A, Singh A, Sen D (2016) Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010–2015). Stem Cell Res Ther 7(1):82CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD, Lyle R, Ibberson M, De Palma M (2014) Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep 8:1432–1446CrossRefPubMedGoogle Scholar
  41. 41.
    Takahashi K, Yan IK, Kim C, Kim J, Patel T (2014) Analysis of extracellular RNA by digital PCR. Front Radiat Ther Oncol 4:129Google Scholar
  42. 42.
    Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593CrossRefPubMedGoogle Scholar
  43. 43.
    Trial J, Entman ML, Cieslik KA (2016) Mesenchymal stem cell-derived inflammatory fibroblasts mediate interstitial fibrosis in the aging heart. J Mol Cell Cardiol 91:28–34CrossRefPubMedGoogle Scholar
  44. 44.
    Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M (2014) Sorting it out: regulation of exosome loading. Semin Cancer Biol 28:3–13CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Vrijsen KR, Maring JA, Chamuleau SAJ, Verhage V, Mol EA, Deddens JC, Metz CHG, Lodder K, van Eeuwijk ECM, van Dommelen SM, Doevendans PA, Smits AM, Goumans M-J, Sluijter JPG (2016) Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv Healthc Mater 5:2555–2565CrossRefPubMedGoogle Scholar
  46. 46.
    Waldenström A, Gennebäck N, Hellman U, Ronquist G (2012) Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells. PLoS One 7:e34653CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wang X, Gu H, Huang W, Peng J, Li Y, Yang L, Qin D, Essandoh K, Wang Y, Peng T, Fan G-C (2016) Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice. Diabetes 65:3111–3128CrossRefPubMedGoogle Scholar
  48. 48.
    Wang X, Huang W, Liu G, Cai W, Millard RW, Wang Y, Chang J, Peng T, Fan G-C (2014) Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. J Mol Cell Cardiol 74:139–150CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Wang Y, Zhang L, Li Y, Chen L, Wang X, Guo W, Zhang X, Qin G, He S, Zimmerman A, Liu Y, Kim I, Weintraub NL, Tang Y (2015) Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 192:61–69CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Xu X, Tan X, Hulshoff MS, Wilhelmi T, Zeisberg M, Zeisberg EM (2016) Hypoxia-induced endothelial-mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells. FEBS Lett 590:1222–1233CrossRefPubMedGoogle Scholar
  51. 51.
    Xu X, Tan X, Tampe B, Sanchez E, Zeisberg M, Zeisberg EM (2015) Snail is a direct target of hypoxia-inducible factor 1α (HIF1α) in hypoxia-induced endothelial to mesenchymal transition of human coronary endothelial cells. J Biol Chem 290:16653–16664CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Yu B, Kim HW, Gong M, Wang J, Millard RW, Wang Y, Ashraf M, Xu M (2015) Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 182:349–360CrossRefPubMedGoogle Scholar
  53. 53.
    Yu X, Deng L, Wang D, Li N, Chen X, Cheng X, Yuan J, Gao X, Liao M, Wang M, Liao Y (2012) Mechanism of TNF-α autocrine effects in hypoxic cardiomyocytes: initiated by hypoxia inducible factor 1α, presented by exosomes. J Mol Cell Cardiol 53:848–857CrossRefPubMedGoogle Scholar
  54. 54.
    Zhang X, Wang X, Zhu H, Kranias EG, Tang Y, Peng T, Chang J, Fan G-C (2012) Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. PLoS One 7:e32765CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    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:e002856CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Cardiovascular SciencesKU LeuvenLeuvenBelgium

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