The Development and Regeneration of Coronary Arteries

  • Lingjuan He
  • Bin ZhouEmail author
Regenerative Medicine (SM Wu, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Regenerative Medicine


Purpose of Review

In this review, we aim to summarize and discuss the cellular origins of the coronary endothelial cells during development and neovascularization in the adult stage after cardiac injury.

Recent findings

Recent work identified three different developmental origins for coronary endothelial cells: proepicardium, endocardium, and sinus venosus. However, the level of contribution by each source remains debated. During heart injury and regeneration, although multiple cell types such as endothelial progenitor cells, epicardial cells, and endocardial cells were reported to contribute neovascularization, convincing evidence is still lacking.. Recently, fibroblasts were reported to contribute to endothelial cells after cardiac injury through mesenchymal-to-endothelial transition. A subsequent study demonstrated that pre-existing endothelial cells mainly mediate cardiac neovascularization after injury.


The developmental origins of coronary vessels are diverse and further studies are needed to address the exact contribution from each source and the molecular mechanism governing distinct vessel formation programs. In the adult stage, neovascularization is mainly mediated by the pre-existing endothelial cells, with negligible contribution from other sources.


Coronary artery Cellular origins Genetic lineage tracing Coronary heart disease 



This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS, XDB19000000, XDA16020204), National Science Foundation of China (31730112, 91639302, 31625019, 81761138040, 31701292),

Compliance with Ethical Standards

Conflict of Interest

Lingjuan He and Bin Zhou declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

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


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart Disease and Stroke Statistics–2017 Update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.Google Scholar
  2. 2.
    Lluri G, Aboulhosn J. Coronary arterial development: a review of normal and congenitally anomalous patterns. Clin Cardiol. 2014;37(2):126–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Red-Horse K, Ueno H, Weissman IL, Krasnow MA. Coronary arteries form by developmental reprogramming of venous cells. Nature. 2010;464(7288):549–53.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111(25):3481–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Tabas I, Garcia-Cardena G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol. 2015;209(1):13–22.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Potluri R, Baig M, Mavi JS, Ali N, Aziz A, Uppal H, et al. The role of angioplasty in patients with acute coronary syndrome and previous coronary artery bypass grafting. Int J Cardiol. 2014;176(3):760–3.Google Scholar
  7. 7.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.CrossRefPubMedGoogle Scholar
  8. 8.
    Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142(3):375–86.Google Scholar
  9. 9.
    Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485(7400):593–8.Google Scholar
  10. 10.
    Margariti A, Winkler B, Karamariti E, Zampetaki A, Tsai TN, Baban D, et al. Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels. Proc Natl Acad Sci U S A. 2012;109(34):13793–8.Google Scholar
  11. 11.
    Han JK, Chang SH, Cho HJ, Choi SB, Ahn HS, Lee J, et al. Direct conversion of adult skin fibroblasts to endothelial cells by defined factors. Circulation. 2014;130(14):1168–78.Google Scholar
  12. 12.
    Souders CA, Bowers SL, Baudino TA. Cardiac fibroblast: the renaissance cell. Circ Res. 2009;105(12):1164–76.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ratajska A, Czarnowska E, Ciszek B. Embryonic development of the proepicardium and coronary vessels. Int J Dev Biol. 2008;52(2/3):229–36.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I, Rivera-Feliciano J, et al. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature. 2008;454(7200):109–13.Google Scholar
  15. 15.
    Perez-Pomares JM, Phelps A, Sedmerova M, Carmona R, Gonzalez-Iriarte M, Munoz-Chapuli R, et al. Experimental studies on the spatiotemporal expression of WT1 and RALDH2 in the embryonic avian heart: a model for the regulation of myocardial and valvuloseptal development by epicardially derived cells (EPDCs). Dev Biol. 2002;247(2):307–26.Google Scholar
  16. 16.
    Manner J. Does the subepicardial mesenchyme contribute myocardioblasts to the myocardium of the chick embryo heart? A quail-chick chimera study tracing the fate of the epicardial primordium. Anat Rec. 1999;255(2):212–26.CrossRefPubMedGoogle Scholar
  17. 17.
    Kretzschmar K, Watt FM. Lineage tracing. Cell. 2012;148(1/2):33–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Cai CL, Martin JC, Sun Y, Cui L, Wang L, Ouyang K, et al. A myocardial lineage derives from Tbx18 epicardial cells. Nature. 2008;454(7200):104–8.Google Scholar
  19. 19.
    Katz TC, Singh MK, Degenhardt K, Rivera-Feliciano J, Johnson RL, Epstein JA, et al. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev Cell. 2012;22(3):639–50.Google Scholar
  20. 20.
    Sheikh AY, Chun HJ, Glassford AJ, Kundu RK, Kutschka I, Ardigo D, et al. In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure. Am J Physiol Heart Circ Physiol. 2008;294(1):H88–98.Google Scholar
  21. 21.
    Tian X, Hu T, Zhang H, He L, Huang X, Liu Q, et al. Subepicardial endothelial cells invade the embryonic ventricle wall to form coronary arteries. Cell Res. 2013;23(9):1075–90.Google Scholar
  22. 22.
    Chen HI, Sharma B, Akerberg BN, Numi HJ, Kivela R, Saharinen P, et al. The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis. Development. 2014;141(23):4500–12.Google Scholar
  23. 23.
    Wu B, Zhang Z, Lui W, Chen X, Wang Y, Chamberlain AA, et al. Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling. Cell. 2012;151(5):1083–96.Google Scholar
  24. 24.
    Zhang H, Pu W, Li G, Huang X, He L, Tian X, et al. Endocardium minimally contributes to coronary endothelium in the embryonic ventricular free walls. Circ Res. 2016;118(12):1880–93.Google Scholar
  25. 25.
    Combs MD, Braitsch CM, Lange AW, James JF, Yutzey KE. NFATC1 promotes epicardium-derived cell invasion into myocardium. Development. 2011;138(9):1747–57.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sharma B, Ho L, Ford GH, Chen HI, Goldstone AB, Woo YJ, et al. Alternative progenitor cells compensate to rebuild the coronary vasculature in Elabela- and Apj-deficient hearts. Dev Cell. 2017;42(6):655–66. e653Google Scholar
  27. 27.
    •• Tian X, Hu T, Zhang H, He L, Huang X, Liu Q, et al. Vessel formation. De novo formation of a distinct coronary vascular population in neonatal heart. Science. 2014;345(6192):90–4. This study discovers that a substantial number of coronary vessels form de novo after birth, and they are derived from endocardial cells. Google Scholar
  28. 28.
    He L, Tian X, Zhang H, Wythe JD, Zhou B. Fabp4-CreER lineage tracing reveals two distinctive coronary vascular populations. J Cell Mol Med. 2014;18(11):2152–6.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Moorman AF, Christoffels VM. Cardiac chamber formation: development, genes, and evolution. Physiol Rev. 2003;83(4):1223–67.CrossRefPubMedGoogle Scholar
  30. 30.
    Han P, Bloomekatz J, Ren J, Zhang R, Grinstein JD, Zhao L, et al. Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis. Nature. 2016;534(7609):700–4.Google Scholar
  31. 31.
    Tian X, Li Y, He L, Zhang H, Huang X, Liu Q, et al. Identification of a hybrid myocardial zone in the mammalian heart after birth. Nat Commun. 2017;8(1):87.Google Scholar
  32. 32.
    Sedmera D, Pexieder T, Vuillemin M, Thompson RP, Anderson RH. Developmental patterning of the myocardium. Anat Rec. 2000;258(4):319–37.CrossRefPubMedGoogle Scholar
  33. 33.
    Cochain C, Channon KM, Silvestre JS. Angiogenesis in the infarcted myocardium. Antioxid Redox Signal. 2013;18(9):1100–13.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.Google Scholar
  35. 35.
    Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5(4):434–8.Google Scholar
  36. 36.
    Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K, et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood. 2004;104(9):2752–60.Google Scholar
  37. 37.
    Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res. 2012;110(4):624–37.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol. 2004;24(2):288–93.Google Scholar
  39. 39.
    Smart N, Bollini S, Dube KN, Vieira JM, Zhou B, Davidson S, et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011;474(7353):640–4.Google Scholar
  40. 40.
    Zhou B, Honor LB, He H, Ma Q, Oh JH, Butterfield C, et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest. 2011;121(5):1894–904.Google Scholar
  41. 41.
    Russell JL, Goetsch SC, Gaiano NR, Hill JA, Olson EN, Schneider JW. A dynamic notch injury response activates epicardium and contributes to fibrosis repair. Circ Res. 2011;108(1):51–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Smart N, Risebro CA, Clark JE, Ehler E, Miquerol L, Rossdeutsch A, et al. Thymosin beta4 facilitates epicardial neovascularization of the injured adult heart. Ann N Y Acad Sci. 2010;1194:97–104.Google Scholar
  43. 43.
    Dube KN, Thomas TM, Munshaw S, Rohling M, Riley PR, Smart N. Recapitulation of developmental mechanisms to revascularize the ischemic heart. JCI Insight. 2017;2(22).
  44. 44.
    Winter EM, Grauss RW, Hogers B, van Tuyn J, van der Geest R, Lie-Venema H, et al. Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart. Circulation. 2007;116(8):917–27.Google Scholar
  45. 45.
    Kakkar R, Lee RT. Intramyocardial fibroblast myocyte communication. Circ Res. 2010;106(1):47–57.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    • Ubil E, Duan J, Pillai IC, Rosa-Garrido M, Wu Y, Bargiacchi F, et al. Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature. 2014;514(7524):585–90. This study concludes that a substantial number of fibroblasts give rise to coronary endothelial cells after cardiac injury. Google Scholar
  47. 47.
    Zheng B, Zhang Z, Black CM, de Crombrugghe B, Denton CP. Ligand-dependent genetic recombination in fibroblasts: a potentially powerful technique for investigating gene function in fibrosis. Am J Pathol. 2002;160(5):1609–17.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    •• He L, Huang X, Kanisicak O, Li Y, Wang Y, Li Y, et al. Pre-existing endothelial cells mediate cardiac neovascularization after injury. J Clin Invest. 2017;127(8):2968–81. This study provides comprehensive genetic lineage tracing evidence showing that coronary endothelial cells mainly mediate neovascularization after cardiac injury. Google Scholar
  49. 49.
    Kong P, Christia P, Saxena A, Su Y, Frangogiannis NG. Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am J Physiol Heart Circ Physiol. 2013;305(9):H1363–72.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zhang H, Lui KO, Zhou B. Endocardial cell plasticity in cardiac development, diseases and regeneration. Circ Res. 2018;122(5):774–89.CrossRefPubMedGoogle Scholar
  51. 51.
    Miquerol L, Thireau J, Bideaux P, Sturny R, Richard S, Kelly RG. Endothelial plasticity drives arterial remodeling within the endocardium after myocardial infarction. Circ Res. 2015;116(11):1765–71.CrossRefPubMedGoogle Scholar
  52. 52.
    Tang J, Zhang H, He L, Huang X, Li Y, Pu W, et al. Genetic fate mapping defines the vascular potential of endocardial cells in the adult heart. Circ Res. 2018;122(7):984–93.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The State Key Laboratory of Cell Biology, CAS Center for Excellence on Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghaiChina
  2. 2.Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological SciencesUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
  3. 3.School of Life Science and TechnologyShanghaiTech UniversityShanghaiChina
  4. 4.Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative MedicineJinan UniversityGuangzhouChina

Personalised recommendations