Abstract
Cardiovascular development has become a crucial element of transgene technology in that many transgenic and knockout mice unexpectedly present with a cardiac phenotype, which often turns out to be embryolethal. This demonstrates that formation of the heart and the connecting vessels is essential for the functioning vertebrate organism. The embryonic mesoderm is the source of both the cardiogenic plate, giving rise to the future myocardium as well as the endocardium that will line the system on the inner side. Genetic cascades are unravelled that direct dextral looping and subsequent secondary looping and wedging of the outflow tract of the primitive heart tube. This tube consists of a number of transitional zones and intervening primitive cardiac chambers. After septation and valve formation, the mature two atria and two ventricles still contain elements of the primitive chambers as well as transitional zones. An essential additional element is the contribution of extracardiac cell populations like neural crest cells and epicardium-derived cells. Whereas the neural crest cell is of specific importance for outflow tract septation and formation of the pharyngeal arch arteries, the epicardium-derived cells are essential for proper maturation of the myocardium and coronary vascular formation. Inductive signals, sometimes linked to apoptosis, of the extracardiac cells are thought to be instructive for differentiation of the conduction system. In summary, cardiovascular development is a complex interplay of many cell–cell and cell–matrix interactions. Study of both (transgenic) animal models and human pathology is unravelling the mechanisms underlying congenital cardiac anomalies.
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References
Moorman AFM, Christoffels VM 2003 Cardiac chamber formation: development, genes and evolution. Physiol Rev 83: 223–1267
Levin M, Pagan S, Roberts DJ, Cooke J, Kuehn MR, Tabin CJ 1997 Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo. Dev Biol 189: 7–67
Olson EN, Srivastava D 1996 Molecular pathways controlling heart development. Science 272: 71–676
Yutzey C, Rhee JT, Bader D 1994 Expression of the atrial-specific myosin heavy chain AMHC1 and the establishment of anteroposterior polarity in the developing chicken heart. Development 120: 71–883
Poelmann RE, Gittenberger-de Groot AC 1999 A subpopulation of apoptosis-prone cardiac neural crest cells targets to the venous pole: multiple functions in heart development?. Dev Biol 207: 71–286
Poelmann RE, Mikawa T, Gittenberger-de Groot AC 1998 Neural crest cells in outflow tract septation of the embryonic chicken heart: differentiation and apoptosis. Dev Dyn 212: 73–384
Bergwerff M, Verberne ME, DeRuiter MC, Poelmann RE, Gittenberger-de Groot AC 1998 Neural crest cell contribution to the developing circulatory system. Implications for vascular morphology?. Circ Res 82: 21–231
Waldo K, Miyagawa-Tomita S, Kumiski D, Kirby ML 1998 Cardiac neural crest cells provide new insight into septation of the cardiac outflow tract: Aortic sac to ventricular septal closure. Dev Biol 196: 29–144
Virágh Sz, Gittenberger-de Groot AC, Poelmann RE, Kálmán F 1993 Early development of quail heart epicardium and associated vascular and glandular structures. Anat Embryol 188: 81–393
Gittenberger-de Groot AC, Vrancken Peeters MPFM, Mentink MMT, Gourdie RG, Poelmann RE 1998 Epicardial derived cells, EPDCs, contribute a novel population to the myocardial wall and the atrioventricular cushions. Circ Res 82: 043–1052
Männer J 1999 Does the subepicardial mesenchyme contribute myocardioblasts to the myocardium of the chick embryo heart? A quail-chick chimera study tracing the fate op the epicardial primordium. Anat Rec 255: 12–226
Pexieder T, Wenink ACG, Anderson RH 1989 A suggested nomenclature for the developing heart. Int J Cardiol 25: 55–264
Stainier DYR, Fouquet B, Chen J-N, Warren KS, Weinstein BM, Meiler SE, Mohideen MAPK, Neuhauss CF, Solnica-Krezel L, Schier AF, Zwartkruis F, Stemple DL, Malicki J, Driever W, Fishman MC 1996 Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. Development 123: 85–292
Laverriere AC, Macniell C, Mueller C, Poelmann RE, Burch JBE, Evans T 1994 GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut. J Biol Chem 269: 3177–23184
DeRuiter MC, Poelmann RE, VanderPlas-de Vries I, Mentink MMT, Gittenberger-de Groot AC 1992 The development of the myocardium and endocardium in mouse embryos. Fusion of two heart tubes?. Anat Embryol 185: 61–473
Christoffels VM, Habets PEMH, Franco D, Campione M, DeJong F, Lamers WH, Bao ZZ, Palmer S, Biben C, Harvey RP, Moorman AFM 2000 Chamber formation and morphogenesis in the developing mammalian heart. Dev Biol 223: 66–278
van den Hoff MJ, Kruithof BP, Moorman AF, Markwald RR, Wessels A 2001 Formation of myocardium after the initial development of the linear heart tube. Dev Biol 240: 1–76
Anderson RH, Webb S, Brown NA 1999 Clinical anatomy of the atrial septum with reference to its developmental components. Clin Anat 12: 62–374
DeRuiter MC, Gittenberger-de Groot AC, Wenink ACG, Poelmann RE, Mentink MMT 1995 In normal development pulmonary veins are connected to the sinus venosus segment in the left atrium. Anat Rec 243: 4–92
Tasaka H, Krug EL, Markwald RR 1996 Origin of the pulmonary venous orifice in the mouse and its relation to the morphogenesis of the sinus venosus, extracardiac mesenchyme (spina vestibuli), and atrium. Anat Rec 246: 07–113
Aoyama N, Tamaki H, Kikawada R, Yamashina S 1995 Development of the conduction system in the rat heart as determined by leu-7 (HNK-1) immunohistochemistry and computer graphics reconstruction. Lab Invest 72: 55–366
Wenink ACG, Symersky P, Ikeda T, DeRuiter MC, Poelmann RE, Gittenberger-de Groot AC 2000 HNK-1 expression patterns in the embryonic rat heart distinguish between sinuatrial tissues and atrial myocardium. Anat Embryol 201: 9–50
Blom NA, Gittenberger-de Groot AC, DeRuiter MC, Poelmann RE, Mentink MM, Ottenkamp J 1999 Development of the cardiac conduction tissue in human embryos using HNK-1 antigen expression: possible relevance for understanding of abnormal atrial automaticity. Circulation 99: 00–806
Blom NA, Gittenberger-de Groot AC, Jongeneel TH, DeRuiter MC, Poelmann RE, Ottenkamp J 2001 Normal development of the pulmonary veins in human embryos and formulation of a morphogenetic concept for sinus venosus defects. Am J Cardiol 87: 05–309
Webb S, Brown N, Wessels A, Anderson RH 1998 Development of the murine pulmonary vein and its relationship to the embryonic venous sinus. Anat Rec 250: 25–334
Bartram U, Molin DGM, Wisse LJ, Mohamad A, Sanford LP, Doetschman T, Speer CP, Poelmann RE, Gittenberger-de Groot AC 2001 Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGFβ2-knockout mice. Circulation 103: 745–2752
Gittenberger-de Groot AC, Bartram U, Oosthoek PW, Bartelings MM, Hogers B, Poelmann RE, Jongewaard IN, Klewer SE 2003 Collagen type VI expression during cardiac development and in human fetuses with trisomy 21. Anat Rec 275A: 109–1116
Blom NA, Ottenkamp J, Wenink AG, Gittenberger-de Groot AC 2003 Deficiency of the vestibular spine in atrioventricular septal defects in human fetuses with down syndrome. Am J Cardiol 91: 80–184
Woodrow Benson D, Sharkey A, Fatkin D, Lang P, Basson CT, McDonough B, Strauss AW, Seidman JG, Seidman CE 1998 Reduced penetrance, variable expressivity and genetic heterogeneity of familial atrial septal defects. Circulation 97: 043–2048
Gittenberger-de Groot AC, DeRuiter MC, Bartelings MM, Poelmann RE 2001 Embryology of congenital heart disease. In: Crawford MH, DiMarco JP (eds) Cardiology. Mosby International Limited: London p 2.1–2.10
Wenink ACG, Wisse BJ, Groenendijk PM 1994 Development of the inlet portion of the right ventricle in the embryonic rat heart: the basis for tricuspid valve development. Anat Rec 239: 16–223
Lamers WH, Virágh Sz, Wessels A, Moorman AFM, Anderson RH 1995 Formation of the tricuspid valve in the human heart. Circulation 91: 11–121
Webb S, Brown NA, Anderson RH 1997 Cardiac morphology at late fetal stages in the mouse with trisomy 16: consequences for different formation of the atrioventricular junction when compared to humans with trisomy 21. Cardiovasc Res 34: 15–524
Mikawa T, Gourdie RG 1996 Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev Biol 174: 21–232
Laane HM 1978 The arterial pole of the embryonic heart I Nomenclature of the arterial pole of the embryonic heart II Septation of the arterial pole of the embryonic heart. Acta Morphol Neerl Scand 1033–1037
Bartelings MM, Wenink ACG, Gittenberger-de Groot AC, Oppenheimer-Dekker A 1986 Contribution to the aortopulmonary septum to the muscular outlet septum in the human heart. Acta Morphol Neerl Scand 24: 81–192
Boot MJ, Gittenberger-de Groot AC, van Iperen L, Hierck BP, Poelmann RE 2003 Spatiotemporally separated cardiac neural crest subpopulations that target the outflow tract septum and pharyngeal arch arteries. Anat Rec 275A: 009–1018
Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM 2000 Fate of the mammalian cardiac neural crest. Development 127: 607–1616
Waldo KL, Lo CW, Kirby ML 1999 Connexin 43 expression reflects neural crest patterns during cardiovascular development. Dev Biol 208: 07–323
Epstein JA, Li J, Lang D, Chen F, Brown CB, Jin F, Lu MM, Thomas M, Liu E, Wessels A, Lo CW 2000 Migration of cardiac neural crest cells in Splotch embryos. Development 127: 869–1878
Kirby ML, Gale TF, Stewart DE 1983 Neural crest cells contribute to normal aorticopulmonary septation. Science 220: 059–1061
Gittenberger-de Groot AC, Bartelings MM, Bogers AJJC, Boot MJ, Poelmann RE 2002 The embryology of the common arterial trunk. Prog Pediatr Cardiol 15: 1–8
Gruber PJ, Kubalak SW, Pexieder T, Sucov HM, Evans RM, Chien KR 1996 RXRα Deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice. J Clin Invest 98: 332–1343
Hogers B, DeRuiter MC, Gittenberger-de Groot AC, Poelmann RE 1997 Unilateral vitelline vein ligation alters intracardiac blood flow patterns and morphogenesis in the chick embryo. Circ Res 80: 73–481
Lindsay EA, Vitelli F, Su H, Morishima M, Huynh T, Pramparo T, Jurecic V, Ogunrinu G, Sutherland HF, Scambler PJ, Bradley A, Baldini A 2001 Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410: 7–101
Waldo K, Kumiski DH, Wallis KT, Stadt HA, Hutson MR, Platt DH, Kirby ML 2001 Conotruncal myocardium arises from a secondary heart field. Development 128: 179–3188
Deleted in proof.
Kelly RG, Buckingham ME 2002 The anterior heart-forming field: voyage to the arterial pole of the heart. Trends Genet 18: 10–216
Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, Kamatani N, Momma K, Takao A, Nakazawa M, Shimizu N, Matsuoka R 2003 Role of TBX1 in human del22q11.2 syndrome. Lancet 362: 366–1373
Yamagishi C, Hierck BP, Gittenberger-de Groot AC, Yamagishi H, Srivastava D 2003 Functional attenuation of Ufd1L, a 22q11.2 deletion syndrome candidate gene, leads to defects of cardiac outflow septation in chicken embryos. Pediatr Res 53: 1–8
Stalmans I, Lambrechts D, Desmet F, Jansen S, Wang J, Maity S, Kneer P, von der Ohe M, Swillen A, Maes C, Gewillig M, Molin DGM, Hellings P, Boetel T, Haardt M, Compernolle V, Dewerchin M, Vlietinck R, Emanuel B, Gittenberger-de Groot AC, Esguerra CV, Scambler P, Morrow B, Driscoll DA, Moons L, Carmeliet G, Behn-Krappa A, DeVviendt K, Collen D, Conway SJ, Carmeliet P 2003 VEGF: a modifier of the del22q11 (DiGeorge) syndrome?. Nat Med 9: 73–182
Siman CM, Gittenberger-de Groot AC, Wisse BJ, Eriksson UJ 2000 Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment. Teratology 61: 55–367
Nakajima Y, Morishima M, Nakazawa M, Momma K 1996 Inhibition of outflow cushion mesenchyme formation in retinoic acid-induced complete transposition of the great arteries. Cardiovasc Res 31: 77–E85
Costell M, Carmona R, Gustafsson E, Gonzalez-Iriarte M, Fassler R, Munoz-Chapuli R 2002 Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice. Circ Res 91: 58–164
Wessels A, Vermeulen JL, Verbeek FJ, Virágh Sz, Kalman F, Lamers WH, Moorman AFM 1992 Spatial distribution of “tissue-specific” antigens in the developing human heart and skeletal muscle. III. An immunohistochemical analysis of the distribution of the neural tissue antigen G1N2 in the embryonic heart; implications for the development of the atrioventricular conduction system. Anat Rec 232: 7–111
Rentschler S, Vaidya DM, Tamaddon H, Degenhardt K, Sassoon D, Morley GE, Jalife J, Fishman GI 2001 Visualization and functional characterization of the developing murine cardiac conduction system. Development 128: 785–1792
Rentschler S, Zander J, Meyers K, France D, Levine R, Porter G, Rivkees SA, Morley GE, Fishman GI 2002 Neuregulin-1 promotes formation of the murine cardiac conduction system. Proc Natl Acad Sci U S A 99: 0464–10469
Gittenberger-de Groot AC, Blom NM, Aoyama N, Sucov H, Wenink AC, Poelmann RE 2003 The role of neural crest and epicardium-derived cells in conduction system formation. Novartis Found Symp 250: 25–134
Jongbloed MRM, Schalij MJ, Poelmann RE, Blom NA, Fekkes ML, Wang Z, Fishman GI, Gittenberger-de-Groot AC 2004 Embryonic conduction tissue: a spatial correlation with adult arrhythmogenic areas? Transgenic CCS/lacZ expression in the cardiac conduction system of murine embryos. J Cardiovasc Electrophysiol 15: 49–555
Kanzawa N, Poma CP, Takebayashi-Suzuki K, Diaz KG, Layliev J, Mikawa T 2002 Competency of embryonic cardiomyocytes to undergo Purkinje fiber differentiation is regulated by endothelin receptor expression. Development 129: 185–3194
Drake CJ, Hungerford JE, Little CD 1998 Morphogenesis of the first blood vessels. Ann N Y Acad Sci 857: 55–179
DeRuiter MC, Gittenberger-de Groot AC, Poelmann RE, van Iperen L, Mentink MMT 1993 Development of the pharyngeal arch system related to the pulmonary and bronchial vessels in the avian embryo. Circulation 87: 306–1319
Molin DGM, DeRuiter MC, Wisse LJ, Mohamad A, Doetschman T, Poelmann RE, Gittenberger-de Groot AC 2002 Altered apoptosis pattern during pharyngeal arch artery remodelling is associated with aortic arch malformations in Tgf beta 2 knock-out mice. Cardiovasc Res 56: 12–322
Bergwerff M, DeRuiter MC, Hall S, Poelmann RE, Gittenberger-de Groot AC 1999 Unique vascular morphology of the fourth aortic arches: possible implications for pathogenesis of type-B aortic arch interruption and anomalous right subclavian artery. Cardiovasc Res 44: 85–196
Hierck BP, Molin DGM, Boot MJ, Poelman RE, Gittenberger-de Groot AC 2004 A chicken model for DGCR6 as a modifier gene in the DiGeorge critical region. Pediatr Res 56: 40–448
Vrancken Peeters M-PFM, Mentink MMT, Poelmann RE, Gittenberger-de Groot AC 1995 Cytokeratins as a marker for epicardial formation in the quail embryo. In: Cardiovascular Development Meeting University of Rochester
Vrancken Peeters MPFM, Gittenberger-de Groot AC, Mentink MMT, Hungerford JE, Little CD, Poelmann RE 1997 The development of the coronary vessels and their differentiation into arteries and veins in the embryonic quail heart. Develop Dynam 208: 38–348
Poelmann RE, Gittenberger-de Groot AC, Mentink MMT, Bökenkamp R, Hogers B 1993 Development of the cardiac coronary vascular endothelium, studied with antiendothelial antibodies, in chicken-quail chimeras. Circ Res 73: 59–568
Bogers AJJC, Gittenberger-de Groot AC, Poelmann RE, Péault BM, Huysmans HA 1989 Development of the origin of the coronary arteries, a matter of ingrowth or outgrowth?. Anat Embryol 180: 37–441
Waldo KL, Willner W, Kirby ML 1990 Origin of the proximal artery stems and a review of ventricular vascularization in the chick embryo. Am J Anat 188: 09–120
Vrancken Peeters MPFM, Gittenberger-de Groot AC, Mentink MMT, Poelmann RE 1999 Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelial-mesenchymal transformation of the epicardium. Anat Embryol 199: 67–378
Dettman RW, Denetclaw W, Ordahl CP, Bristow J 1998 Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. Dev Biol 193: 69–181
Gittenberger-de Groot AC, Vrancken Peeters MPFM, Bergwerff M, Mentink MMT, Poelmann RE 2000 Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation. Circ Res 87: 69–971
Lie-Venema H, Gittenberger-de Groot AC, van Empel LJP, Boot MJ, Kerkdijk H, de Kant E, DeRuiter MC 2003 Ets-1 and Ets-2 transcription factors are essential for normal coronary and myocardial development in chicken embryos. Circ Res 92: 49–756
Gittenberger-de Groot AC, Sauer U, Bindl L, Babic R, Essed CE, Buhlmeyer K 1988 Competition of coronary arteries and ventriculo-coronary arterial communications in pulmonary atresia with intact ventricular septum. Int J Cardiol 18: 43–258
Gittenberger-de Groot AC, Tennstedt C, Chaoui R, Lie-Venema H, Sauer U, Poelmann RE 2001 Ventriculo coronary arterial communications (VCAC) and myocardial sinusoids in hearts with pulmonary artresia with intact ventricular septum: two different diseases. Prog Pediatr Cardiol 13: 57–164
Eriksson UJ, Borg LAH, Forsberg H, Siman CM, Suzuki N, Yang X 1996 Can fetal loss be prevented? The biochemical basis of the diabetic embryopathy. Diabetes Rev 4: 9–69
Boot MJ, Steegers-Theunissen RP, Poelmann RE, van Iperen L, Lindemans J, Gittenberger-de Groot AC 2003 Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro. Dev Dyn 227: 01–308
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Gittenberger-de Groot, A., Bartelings, M., Deruiter, M. et al. Basics of Cardiac Development for the Understanding of Congenital Heart Malformations. Pediatr Res 57, 169–176 (2005). https://doi.org/10.1203/01.PDR.0000148710.69159.61
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DOI: https://doi.org/10.1203/01.PDR.0000148710.69159.61
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