Molecular Pathways and Animal Models of Coronary Artery Anomalies

  • Juan A. Guadix
  • José M. Pérez-Pomares


The coronary vascular system is a sophisticated, highly patterned anatomical entity, and therefore a wide range of congenital malformations of the coronary vasculature has been described. Despite the clinical interest of congenital coronary artery anomalies (CCA), very few attempts have been made to relate specific embryonic developmental mechanisms to the congenital anomalies of these blood vessels. This is so because developmental data about the morphogenesis of the coronary vascular system is derived from complex studies carried out in animals (mostly transgenic mice) and may not be noted by the clinicians who take the care of these patients. We will try to offer embryological explanations for a variety of CCA based on the analysis of multiple animal models for the study of cardiac embryogenesis, and suggest to the reader developmental mechanistic explanations for the pathogenesis of these anomalies.


Coronary artery anomalies CAA Coronary vascular system Embryogenesis Coronary arteries Coronary veins Endothelium Classification Neural crest cells NCC Persistent truncus arteriosus PTA Hes1 Pax3 Pbx1 Tbx1 Epithelial-to-mesenchymal transition EMT Epicardial-derived cells EPDCs TGFβ TGFBR1 Fibroblast growth factor Vangl2 Vcam1 BMP2 Endocardial cells Outflow tract Endocardial cushions 


  1. 1.
    Angelini P (2007) Coronary artery anomalies: an entity in search of an identity. Circulation 115:1296–1305PubMedGoogle Scholar
  2. 2.
    Angelini P (1999) Normal and anomalous coronary arteries in humans. In: Angelini P (ed) Coron. artery anomalies. Lippincott, Williams and Wilkins, Philadelphia, pp 27–150Google Scholar
  3. 3.
    Red-Horse K, Ueno H, Weissman IL, Krasnow M (2010) Coronary arteries form by developmental reprogramming of venous cells. Nature 464:549–553PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Katz TC, Singh MK, Degenhardt K et al (2012) Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev Cell 22:639–650PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Wu B, Zhang Z, Lui W et al (2012) Endocardial cells form the coronary arteries by angiogenesis through myocardial-endocardial VEGF signaling. Cell 151:1083–1096PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Tian X, Hu T, Zhang H et al (2014) De novo formation of a distinct coronary vascular population in neonatal heart. Science 345(80):90–94PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Waldo K, Willner W, Kirby M (1990) Origin of the proximal coronary artery stems and a review of ventricular vascularization in the chick embryo. Am J Anat 188:109–120PubMedCrossRefGoogle Scholar
  8. 8.
    Vrancken Peeters MP, Gittenberger-de Groot AC, Mentink MM et al (1997) Differences in development of coronary arteries and veins. Cardiovasc Res 36:101–110PubMedCrossRefGoogle Scholar
  9. 9.
    Roberts W (1986) Major anomalies of coronary arterial origin seen in adulthood. Am Heart J 111:941–963PubMedCrossRefGoogle Scholar
  10. 10.
    Marcelo KL, Goldie LC, Hirschi KK (2013) Regulation of endothelial cell differentiation and specification. Circ Res 112:1272–1287PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Kirby ML, Waldo KL (1990) Role of neural crest in congenital heart disease. Circulation 82:332–340PubMedCrossRefGoogle Scholar
  12. 12.
    Chai Y, Jiang X, Ito Y et al (2000) Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127:1671–1679PubMedGoogle Scholar
  13. 13.
    Nishibatake M, Kirby ML, Van Mierop LH (1987) Pathogenesis of persistent truncus arteriosus and dextroposed aorta in the chick embryo after neural crest ablation. Circulation 75:255–264PubMedCrossRefGoogle Scholar
  14. 14.
    Epstein JA (1996) Pax3, neural crest and cardiovascular development. Trends Cardiovasc Med 6:255–261PubMedCrossRefGoogle Scholar
  15. 15.
    Chang C-P, Stankunas K, Shang C et al (2008) Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract. Development 135:3577–3586PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    High F, Jain R, Stoller J et al (2009) Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development. J Clin Invest 119:1986–1996PubMedCentralPubMedGoogle Scholar
  17. 17.
    Rochais F, Dandonneau M, Mesbah K et al (2009) Hes1 is expressed in the second heart field and is required for outflow tract development. PLoS One 4, e6267PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Théveniau-Ruissy M, Dandonneau M, Mesbah K et al (2008) The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning. Circ Res 103:142–148PubMedCrossRefGoogle Scholar
  19. 19.
    Bajolle F, Zaffran S, Kelly RG et al (2006) Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries. Circ Res 98:421–428PubMedCrossRefGoogle Scholar
  20. 20.
    Bajolle F, Zaffran S, Meilhac SM et al (2008) Myocardium at the base of the aorta and pulmonary trunk is prefigured in the outflow tract of the heart and in subdomains of the second heart field. Dev Biol 313:25–34PubMedCrossRefGoogle Scholar
  21. 21.
    Costell M, Carmona R, Gustafsson E et al (2002) Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice. Circ Res 91:158–164PubMedCrossRefGoogle Scholar
  22. 22.
    Gonzalez-Iriarte M, Carmona R, Perez-Pomares JM et al (2003) Development of the coronary arteries in a murine model of transposition of great arteries. J Mol Cell Cardiol 35:795–802PubMedCrossRefGoogle Scholar
  23. 23.
    Chiu I, Chu S, Wang J et al (1995) Evolution of coronary artery pattern according to short-axis aortopulmonary rotation: a new categorization for complete transposition of the great arteries. J Am Coll Cardiol 26:250–258PubMedCrossRefGoogle Scholar
  24. 24.
    Houyel L, Bajolle F, Capderou A et al (2013) The pattern of the coronary arterial orifices in hearts with congenital malformations of the outflow tracts: a marker of rotation of the outflow tract during cardiac development? J Anat 222:349–357PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Chen HI, Poduri A, Numi H et al (2014) VEGF-C and aortic cardiomyocytes guide coronary artery stem development. J Clin Invest 124:4899–4914PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Pérez-Pomares JM, de la Pompa JL (2011) Signaling during epicardium and coronary vessel development. Circ Res 109:1429–1442PubMedCrossRefGoogle Scholar
  27. 27.
    Männer J, Pérez-Pomares JM, Macías D, Muñoz-Chápuli R (2001) The origin, formation and developmental significance of the epicardium: a review. Cells Tissues Organs 169:89–103PubMedCrossRefGoogle Scholar
  28. 28.
    Peralta M, Steed E, Harlepp S et al (2013) Heartbeat-driven pericardiac fluid forces contribute to epicardium morphogenesis. Curr Biol 23:1726–1735PubMedCrossRefGoogle Scholar
  29. 29.
    Wessels A, Pérez-Pomares JM (2004) The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells. Anat Rec A Discov Mol Cell Evol Biol 276:43–57PubMedCrossRefGoogle Scholar
  30. 30.
    Pae SH, Dokic D, Dettman RW (2008) Communication between integrin receptors facilitates epicardial cell adhesion and matrix organization. Dev Dyn 237:962–978PubMedCrossRefGoogle Scholar
  31. 31.
    Yang JT, Rayburn H, Hynes RO (1995) Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development 121:549–560PubMedGoogle Scholar
  32. 32.
    Romano LA, Runyan RB (2000) Slug is an essential target of TGFbeta2 signaling in the developing chicken heart. Dev Biol 223:91–102PubMedCrossRefGoogle Scholar
  33. 33.
    Takeichi M, Nimura K, Mori M et al (2013) The transcription factors Tbx18 and Wt1 control the epicardial epithelial-mesenchymal transition through bi-directional regulation of Slug in murine primary epicardial cells. PLoS One 8, e57829PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Trembley MA, Velasquez LS, de Mesy Bentley KL, Small EM (2014) Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels. Development 142:21–30CrossRefGoogle Scholar
  35. 35.
    Sridurongrit S, Larsson J, Schwarts R et al (2008) Signaling via the Tgf-β type I receptor Alk5 in heart development. Dev Biol 322:208–218PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Guadix JA, Ruiz-Villalba A, Lettice L et al (2011) Wt1 controls retinoic acid signalling in embryonic epicardium through transcriptional activation of Raldh2. Development 138:1093–1097PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Von Gise A, Zhou B, Honor LB et al (2011) WT1 regulates epicardial epithelial to mesenchymal transition through β-catenin and retinoic acid signaling pathways. Dev Biol 356:421–431CrossRefGoogle Scholar
  38. 38.
    Pérez-Pomares JM, Phelps A, Sedmerova M et al (2002) 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 247:307–326PubMedCrossRefGoogle Scholar
  39. 39.
    Eralp I, Lie-Venema H, DeRuiter MC et al (2005) Coronary artery and orifice development is associated with proper timing of epicardial outgrowth and correlated Fas ligand associated apoptosis patterns. Circ Res 96:526–534PubMedCrossRefGoogle Scholar
  40. 40.
    Lavine KJ, Ornitz DM (2008) Fibroblast growth factors and Hedgehogs: at the heart of the epicardial signaling center. Trends Genet 24:33–40PubMedCrossRefGoogle Scholar
  41. 41.
    Chen THP, Chang T-C, Kang J-O et al (2002) Epicardial induction of fetal cardiomyocyte proliferation via a retinoic acid-inducible trophic factor. Dev Biol 250:198–207PubMedCrossRefGoogle Scholar
  42. 42.
    Del Monte G, Casanova JC, Guadix JA et al (2011) Differential Notch signaling in the epicardium is required for cardiac inflow development and coronary vessel morphogenesis. Circ Res 108:824–836PubMedCrossRefGoogle Scholar
  43. 43.
    Stuckmann I, Evans S, Lassar AB (2003) Erythropoietin and retinoic acid, secreted from the epicardium, are required for cardiac myocyte proliferation. Dev Biol 255:334–349PubMedCrossRefGoogle Scholar
  44. 44.
    Wu H, Lee SH, Gao J et al (1999) Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development 126:3597–3605PubMedGoogle Scholar
  45. 45.
    Wu S, Dong X, Regan J et al (2013) Tbx18 regulates development of the epicardium and coronary vessels. Dev Biol 383:307–320PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Lavine KJ, White AC, Park C et al (2006) Fibroblast growth factor signals regulate a wave of Hedgehog activation that is essential for coronary vascular development. Genes Dev 20:1651–1666PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Smith CL, Baek ST, Sung CY, Tallquist MD (2011) Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ Res 108:e15–e26PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Jeansson M, Gawlik A, Anderson G et al (2011) Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest 121:2278–2289PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Kwee L, Baldwin HS, Shen HM et al (1995) Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice. Development 121:489–503PubMedGoogle Scholar
  50. 50.
    Phillips HM, Rhee HJ, Murdoch JN et al (2007) Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization. Circ Res 101:137–145PubMedCrossRefGoogle Scholar
  51. 51.
    Tevosian SG, Deconinck AE, Tanaka M et al (2000) FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell 101:729–739PubMedCrossRefGoogle Scholar
  52. 52.
    Li WEI, Waldo K, Linask KL et al (2002) An essential role for connexin43 gap junctions in mouse coronary artery development. Development 129:2031–2042PubMedGoogle Scholar
  53. 53.
    Grieskamp T, Rudat C, Lüdtke TH-W et al (2011) Notch signaling regulates smooth muscle differentiation of epicardium-derived cells. Circ Res 108:813–823PubMedCrossRefGoogle Scholar
  54. 54.
    Acharya A, Baek ST, Huang G et al (2012) The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 139:2139–2149PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Van Wijk B, Van Den Berg G, Abu-Issa R et al (2009) Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein- and fibroblast growth factor-signaling pathways. Circ Res 105:431–441PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Landerholm TE, Dong XR, Lu J et al (1999) A role for serum response factor in coronary smooth muscle differentiation from proepicardial cells. Development 126:2053–2062PubMedGoogle Scholar
  57. 57.
    Lu J, Landerholm TE, Wei JS et al (2001) Coronary smooth muscle differentiation from proepicardial cells requires rhoA-mediated actin reorganization and p160 rho-kinase activity. Dev Biol 240:404–418PubMedCrossRefGoogle Scholar
  58. 58.
    Azambuja AP, Portillo-Sánchez V, Rodrigues M et al (2010) Retinoic acid and VEGF delay smooth muscle relative to endothelial differentiation to coordinate inner and outer coronary vessel wall morphogenesis. Circ Res 107:204–216PubMedCrossRefGoogle Scholar
  59. 59.
    Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91PubMedCrossRefGoogle Scholar
  60. 60.
    Kitsukawa T, Shimono A, Kawakami A et al (1995) Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 121:4309–4318PubMedGoogle Scholar
  61. 61.
    Moore AW, McInnes L, Kreidberg J et al (1999) YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development 126:1845–1857PubMedGoogle Scholar
  62. 62.
    Merki E, Zamora M, Raya A et al (2005) Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. Proc Natl Acad Sci U S A 102:18455–18460PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Kane GC, Lam C-F, O’Cochlain F et al (2006) Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia. FASEB J 20:2271–2280PubMedCrossRefGoogle Scholar
  64. 64.
    Teng B, Ledent C, Mustafa J (2008) Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery. J Mol Cell Cardiol 44:905–914PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Mellgren AM, Smith CL, Olsen GS et al (2008) Platelet-derived growth factor receptor beta signaling is required for efficient epicardial cell migration and development of two distinct coronary vascular smooth muscle cell populations. Circ Res 103:1393–1401PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Langlois D, Hneino M, Bouazza L et al (2010) Conditional inactivation of TGF-beta type II receptor in smooth muscle cells and epicardium causes lethal aortic and cardiac defects. Transgenic Res 19:1069–1082PubMedCrossRefGoogle Scholar
  67. 67.
    Sánchez N, Hill C, Love J et al (2011) The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior. Dev Biol 358:331–343PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Wagner N, Morrison H, Pagnotta S et al (2011) The podocyte protein nephrin is required for cardiac vessel formation. Hum Mol Genet 20:2182–2194PubMedCrossRefGoogle Scholar
  69. 69.
    Cheng Z, Sundberg-Smith LJ, Mangiante LE et al (2011) Focal adhesion kinase regulates smooth muscle cell recruitment to the developing vasculature. Arterioscler Thromb Vasc Biol 31:2193–2202PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Barnes RM, Firulli B, VanDusen J et al (2011) Hand2 loss-of-function in Hand1-expressing cells reveals distinct roles in epicardial and coronary vessel formation. Circ Res 108:940–949PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Lin FJ, You LR, Yu CT et al (2012) Endocardial cushion morphogenesis and coronary vessel development require chicken ovalbumin upstream promoter-transcription factor II. Arterioscler Thromb Vasc Biol 32:e135–e146PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Diman N, Brooks G, Kruithof B et al (2014) Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis. Circ Res 115:834–844PubMedCrossRefGoogle Scholar

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© Springer-Verlag Wien 2016

Authors and Affiliations

  1. 1.Department of Animal Biology, Faculty of SciencesUniversity of MálagaMálagaSpain
  2. 2.Andalusian Center for Nanomedicine and Biotechnology (BIONAND)Campanillas (Málaga)Spain
  3. 3.Instituto de Biomedicina de Málaga (IBIMA)-Hospital Carlos de HayaMálagaSpain

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