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Cardiovascular Development and Angiogenesis in the Early Vertebrate Embryo

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Abstract

Embryonic cardiovascular physiology (as opposed to that of the more developed fetus) is being more closely examined by developmental physiologists to explore the onset of cardiovascular function and its regulation, as opposed to the later maturation of these processes as is typically examined in fetal mammal models. As our understanding of embryonic physiology grows, the dogma that the early embryonic heart serves the same convective bulk transport role that it does in the fetal and adult heart is being carefully evaluated. Experimental approaches have involved genetic, surgical and environmental manipulation, and have revealed that blood flow generated by the early embryonic heart is not required for bulk transport of respiratory gases, nutrients, and wastes. Rather, the very small size of the typical vertebrate embryo enables this critical transport function to be achieved by simple diffusion alone. Surprisingly, however, the heart begins to beat (and so expend valuable energy) well before convective blood circulation is actually required. This review postulates that angiogenesis may be a driving factor for the “early” beat of the heart. Recent experiments examining the effect of increased blood pressure and flow pulsatility on proximal blood vessel development offer initial support for the “synangiotropy” hypothesis, namely that the onset of heart beat occurs synchronously with the need for peripheral angiogenesis. Yet, the complexity of the patterns of angiogenesis (regional variations of opposite sign) suggests that we have much more to be learned about the relationship between angiogenesis and the circulation in vertebrate embryos.

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References

  1. Adams, R. H., and A. Eichmann. Axon guidance molecules in vascular patterning. Cold Spring Harb. Perspect. Biol. 2(5):a001875, 2010.

    Article  Google Scholar 

  2. Axelsson, M., and C. E. Franklin. Elucidating the responses and role of the cardiovascular system in crocodilians during diving: fifty years on from the work of C.G. Wilber. Comp. Biochem. Physiol. A: Mol. Integr. Physiol. 160(1):1–8, 2011.

    Article  Google Scholar 

  3. Bagatto, B., and W. Burggren. A three-dimensional functional assessment of heart and vessel development in the larva of the zebrafish (Danio rerio). Physiol. Biochem. Zool. 79(1):194–201, 2008.

    Article  Google Scholar 

  4. Barrionuevo, W. R., and W. W. Burggren. O2 consumption and heart rate in developing zebrafish (Danio rerio): influence of temperature and ambient O2. Am. J. Physiol. 276:R505–R513, 1999.

    Google Scholar 

  5. Branum, S. R., M. Yamada-Fisher, and W. W. Burggren. Reduced heart rate and cardiac output differentially affect angiogenesis, growth and development in early chicken embryos (Gallus domesticus). Physiol. Biochem. Zool. Revised and resubmitted.

  6. Burggren, W. W. Gas exchange, metabolism and ‘ventilation’ in gelatinous frog egg masses. Physiol. Zool. 58:503–514, 1985.

    Google Scholar 

  7. Burggren, W. W. What is the purpose of the embryonic heart beat? or How facts can ultimately prevail over physiological dogma. Physiol. Biochem. Zool. 77:333–345, 2004.

    Article  Google Scholar 

  8. Burggren, W., and D. A. Crossley, II. Comparative cardiovascular development: improving the conceptual framework. Comp. Biochem. Physiol. A 132:661–674, 2002.

    Google Scholar 

  9. Burggren, W. W., A. P. Farrell, and H. B. Lillywhite. Vertebrate cardiovascular systems. In: Handbook of Comparative Physiology, edited by W. Dantzler. Oxford: Oxford University Press, 1997, pp. 215–308.

  10. Burggren, W. W., and B. Keller, Editors. Development of Cardiovascular Systems: Molecules to Organisms. New York: Cambridge University Press, 1997.

  11. Burggren, W. W., and C. L. Reiber. Evolution of cardiovascular systems. In: The Endothelium: A Comprehensive Reference, edited by W. Aird. Cambridge: Cambridge University Press, 2007.

  12. Burggren, W. W. Hemodynamics and regulation of cardiovascular shunts in reptiles. In: Cardiovascular Shunts: Phylogenetic, Ontogenetic and Clinical Aspects, edited by K. Johansen, and W. Burggren. Copenhagen: Munksgaard, 1985, pp. 121–142.

  13. Burggren, W. W., and P. Territo. Early development of blood oxygen transport. In: Hypoxia and Brain, edited by J. Houston and J. Coates. Burlington, Vermont: Queen City Printer, 1995, pp. 45–56.

  14. Burggren, W. W., S. Khorrami, A. Pinder, and T. Sun. Body, eye and chorioallantoic vessel growth are not dependent upon cardiac output levels in day 3–4 chicken embryos. Am. J. Physiol.: Regul. Integr. Physiol. 287:R1399–R1406, 2004.

    Google Scholar 

  15. Burggren, W. W., and S. Warburton. Patterns of form and function in developing hearts: contributions from non-mammalian vertebrates. Cardioscience 5(3):183–191, 1994.

    Google Scholar 

  16. Burggren, W. W., S. J. Warburton, and M. D. Slivkoff. Interruption of cardiac output does not affect short term growth and metabolism in day 3 and 4 chick embryos. J. Exp. Biol. 203:3831–3838, 2000.

    Google Scholar 

  17. Buschmann, I. R., A. Pries, B. Styp-Rekowska, P. Hillmeister, L. Loufrani, D. Henrion, Y. Shi, A. Duelsner, I. Hoefer, N. Gatzke, H. Wang, K. Lehmann, L. Ulm, Z. Ritter, P. Hauff, R. Hlushchuk, V. Djonov, T. van Veen, and F. le Noble. Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis. Development 137(13):2187–2196, 2010.

    Article  Google Scholar 

  18. Carmeliet, P., V. Ferreira, G. Breier, S. Pollefeyt, L. Kieckens, M. Gertsenstein, M. Fahrig, A. Vandenhoeck, K. Harpal, C. Eberhardt, C. Declercq, J. Pawling, L. Moons, D. Collen, W. Risau, and A. Nagy. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573):435–439, 1996.

    Google Scholar 

  19. Clark, E. B., and N. Hu. Hemodynamics of the developing cardiovascular system. In: Embryonic origins of defective heart development, edited by D. E. Bockman and M. L. Kirby. Ann. N. Y. Acad. Sci. 588:41–47, 1990.

  20. Crossley, II, D., and J. Altimiras. Ontogeny of cholinergic and adrenergic cardiovascular regulation in the domestic chicken (Gallus gallus). Am. J. Physiol. Regul. Integr. Comp. Physiol. 279(3):R1091–R1098, 2000.

    Google Scholar 

  21. Crossley, II, D. A., and W. W. Burggren. Development of cardiac form and function in ectothermic sauropsids. J. Morphol. 270(11):1400–1412, 2009.

    Article  Google Scholar 

  22. Crossley, II, D. A., W. W. Burggren, and J. Altimiras. Cardiovascular regulation during hypoxia in embryos of the domestic chicken Gallus gallus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284(1):R219–R226, 2003.

    Google Scholar 

  23. Crossley, II, D. A., S. S. Jonker, J. W. Hicks, and K. L. Thornburg. Maturation of the angiotensin II cardiovascular response in the embryonic White Leghorn chicken (Gallus gallus). J. Comp. Physiol. B. 180(7):1057–1065, 2010.

    Article  Google Scholar 

  24. Dejours, P. Principles of Comparative Respiratory Physiology. 2nd ed. Amsterdam: Elsevier/North-Holland, 1981.

  25. Djonov, V., O. Baum, and P. H. Burri. Vascular remodeling by intussusceptive angiogenesis. Cell Tiss. Res. 314(1):107–117, 2003.

    Article  Google Scholar 

  26. Dzialowski, E. M., T. Sirsat, S. van der Sterren, and E. Villamor. Prenatal cardiovascular shunts in amniotic vertebrates. Respir. Physiol. Neurobiol. 178(1):66–74, 2011.

    Article  Google Scholar 

  27. Egginton, S. Physiological factors influencing capillary growth. Acta Physiol. 202(3):225–239, 2011.

    Article  Google Scholar 

  28. Farmer, C. G. On the evolution of arterial vascular patterns of tetrapods. J. Morphol. 272(11):1325–1341, 2011.

    Article  Google Scholar 

  29. Ferrara, N., K. Carver-Moore, H. Chen, M. Dowd, L. Lu, K. S. O’Shea, L. Powell-Braxton, K. J. Hillan, and M. W. Moore. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573):439–442, 1996.

    Article  Google Scholar 

  30. Folkman, J. Tumor angiogensis: role in regulation of tumor growth. Symp. Soc. Dev. Biol. 30:43–52, 1974.

    Google Scholar 

  31. Fransen, M. E., and L. F. Lemanski. Studies of heart development in normal and cardiac lethal mutant axolotls: a review. Scanning Microsc. 3(4):1101–1115, 1989.

    Google Scholar 

  32. Fritsche, R., and W. W. Burggren. Developmental responses to hypoxia in larvae of the frog Xenopus laevis. Am. J. Physiol. 271:R912–R917, 1996.

    Google Scholar 

  33. Gibbs, C. L. Mechanical determinants of myocardial oxygen consumption. Clin. Exp. Pharmacol. Physiol. 22(1):1–9, 1995.

    Article  Google Scholar 

  34. Groenendijk, B. C., K. Van der Heiden, B. P. Hierck, and R. E. Poelmann. The role of shear stress on ET-1, KLF2, and NOS-3 expression in the developing cardiovascular system of chicken embryos in a venous ligation model. Physiology (Bethesda) 22:380–389, 2007.

    Google Scholar 

  35. Harvey, E. N. The oxygen consumption of luminous bacteria. J. Gen. Physiol. 11469–11475, 1928.

  36. Hastings, D., and W. W. Burggren. Developmental changes in oxygen consumption regulation in larvae of the South African clawed frog Xenopus laevis. J. Exp. Biol. 198:2465–2475, 1995.

    Google Scholar 

  37. Heinke, J., C. Patterson, and M. Moser. Life is a pattern: vascular assembly within the embryo. Front. Biosci. (Elite Ed). 4:2269–2288, 2012.

  38. Heinke, J., C. Patterson, and M. Moser. Life is a pattern: vascular assembly within the embryo. Front. Biosci. (Elite Ed). 4:2269–2288, 2012.

    Google Scholar 

  39. Hicks, J. W. The physiological and evolutionary significance of cardiovascular shunting patterns in reptiles. News Physiol. Sci. 17:241–245, 2002.

    Google Scholar 

  40. Hinsbergh, V. W. M., and P. Koolwijk. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc. Res. 78:203–212, 2008.

    Article  Google Scholar 

  41. Hoage, T., Y. Ding, and X. Xu. Quantifying cardiac functions in embryonic and adult zebrafish. Methods Mol. Biol. 843:11–20, 2012.

    Article  Google Scholar 

  42. Hou, P.-C. L., and W. W. Burggren. Blood pressures and heart rate during larval development in the anuran amphibian Xenopus laevis. Am. J. Physiol. 269:R1120–R1125, 1995.

    Google Scholar 

  43. Hou, P.-C.L., and W. W. Burggren. Cardiac output and peripheral resistance during larval development in the anuran amphibian Xenopus laevis. Am. J. Physiol. 269:R1126–R1132, 1995b.

  44. Hu, N., and B. B. Keller. Relationship of simultaneous atrial and ventricular pressures in stage 16–27 chick embryos. Am. J. Physiol. 269:H1359–H1362, 1995.

    Google Scholar 

  45. Hu, N., D. Sedmera, H. J. Yost, and E. B. Clark. Structure and function of the developing zebrafish heart. Anat. Rec. 260(2):148–157, 2000.

    Article  Google Scholar 

  46. Ishiwata, T., M. Nakazawa, W. T. Pu, S. G. Tevosian, and S. Izumo. Developmental changes in ventricular diastolic function correlate with changes in ventricular myoarchitecture in normal mouse embryos. Circ. Res. 93(9):857–865, 2003.

    Article  Google Scholar 

  47. Isogai, S., N. D. Lawson, S. Torrealday, M. Horiguchi, and B. M. Weinstein. Angiogenic network formation in the developing vertebrate trunk. Development 130:5281–5290, 2003.

    Article  Google Scholar 

  48. Jones, E. A., F. le Noble, and A. Eichmann. What determines blood vessel structure? Genetic prespecification vs. hemodynamics. Physiology 21:388–395, 2006.

    Article  Google Scholar 

  49. Kaltenbrun, E., P. Tandon, N. M. Amin, L. Waldron, C. Showell, and F. L. Conlon. Xenopus: an emerging model for studying congenital heart disease. Birth Defects Res. A Clin. Mol. Teratol. 91(6):495–510, 2011.

    Article  Google Scholar 

  50. Kaunas, R., H. Kang, and K. J. Bayless. Synergistic regulation of angiogenic sprouting by biochemical factors and wall shear stress. Cell. Mol. Bioeng. 4:547–559, 2011.

    Article  Google Scholar 

  51. Keller, B. B., L. J. Liu, J. P. Tinney, and K. Tobita. Cardiovascular developmental insights from embryos. Ann. N. Y. Acad. Sci. 1101:377–388, 2007.

    Article  Google Scholar 

  52. Keller, B. B., M. J. MacLennan, J. P. Tinney, and M. Yoshigi. In vivo assessment of embryonic cardiovascular dimensions and function in day-10.5 to -14.5 mouse embryos. Circ. Res. 79(2):247–255, 1996.

    Article  Google Scholar 

  53. Kertesz, N., J. Wu, T. H. Chen, H. M. Sucov, and H. Wu. The role of erythropoietin in regulating angiogenesis. Dev. Biol. 276(1):101–110, 2004.

    Article  Google Scholar 

  54. Knudsen, T. B., and N. C. Kleinstreuer. Disruption of embryonic vascular development in predictive toxicology. Birth Defects Res. C Embryo Today 93:312–323, 2011.

    Article  Google Scholar 

  55. Kupperman, E., S. Z. An, N. Osborne, and S. Waldron. Stainier DYR A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development. Nature 406:192–195, 2000.

    Article  Google Scholar 

  56. le Noble, F., C. Klein, A. Tintu, A. Pries, and I. Buschmann. Neural guidance molecules, tip cells, and mechanical factors in vascular development. Cardiovasc. Res. 78:232–241, 2008.

    Article  Google Scholar 

  57. Lee, H. S., J. Han, H. J. Bai, and K. W. Kim. Brain angiogenesis in developmental and pathological processes: regulation, molecular and cellular communication at the neurovascular interface. FEBS J. 276:4622–4635, 2009.

    Article  Google Scholar 

  58. Leese, H. J. Metabolism of the preimplantation embryo: 40 years on. Reproduction 143:417–427, 2012.

    Article  Google Scholar 

  59. Lemanski, L. F., S. M. La France, N. Erginel-Unaltuna, E. A. Luque, S. M. Ward, M. E. Fransen, F. J. Mangiacapra, M. Nakatsugawa, S. L. Lemanski, R. B. Capone, et al. The cardiac mutant gene c in axolotls: cellular, developmental, and molecular studies. Cell. Mol. Biol. Res. 41(4):293–305, 1995.

    Google Scholar 

  60. Liu, J., and D. Y. Stainier. Zebrafish in the study of early cardiac development. Circ. Res. 110(6):870–874, 2012.

    Article  Google Scholar 

  61. Lucitti, J. L., K. Tobita, and B. B. Keller. Arterial hemodynamics and mechanical properties after circulatory intervention in the chick embryo. J. Exp. Biol. 208:1877–1885, 2005.

    Article  Google Scholar 

  62. Männer, J. The anatomy of cardiac looping: a step towards the understanding of the morphogenesis of several forms of congenital cardiac malformations. Clin. Anat. 22(1):21–35, 2009.

    Article  Google Scholar 

  63. Maschhoff, K. L., and H. S. Baldwin. Molecular determinants of neural crest migration. Am. J. Med. Genet. 97(4):280–288, 2000.

    Google Scholar 

  64. Miquerol, L., S. Beyer, and R. G. Kelly. Establishment of the mouse ventricular conduction system. Cardiovasc. Res. 91(2):232–242, 2011.

    Google Scholar 

  65. Mitchell, N. J., and R. S. Seymour. The effects of nest temperature, nest substrate, and clutch size on the oxygenation of embryos and larvae of the Australian moss frog, Bryobatrachus nimbus. Physiol. Biochem. Zool. 76(1):60–71, 2003.

    Article  Google Scholar 

  66. Mohun, T., R. Orford, and C. Shang. The origins of cardiac tissue in the amphibian, Xenopus laevis. Trends Cardiovasc Med. 13(6):244–248, 2003.

    Google Scholar 

  67. Mueller, C. A., and R. S. Seymour. Analysis of cutaneous and internal gill gas exchange morphology in early larval amphibians, Pseudophryne bibronii and Crinia georgiana. J. Comp. Physiol. B. 182(6):813–820, 2012.

    Article  Google Scholar 

  68. Nichelmann, M., J. Höchel, and B. Tzschentke. Biological rhythms in birds—development, insights and perspectives. Comp. Biochem. Physiol. A: Mol. Integr. Physiol. 124(4):429–437, 1999.

    Article  Google Scholar 

  69. Nilsson, S. The crocodilian heart and central hemodynamics. Cardioscience 5(3):163–166, 1994.

    MathSciNet  Google Scholar 

  70. Paff, G. H., R. J. Boucek, and T. C. Harrell. Observations on the development of the electrocardiogram. Anat. Rec. 160:575–582, 1968.

    Article  Google Scholar 

  71. Patan, S. Vasculogenesis and angiogenesis. Cancer Treat. Res. 117A:3–32, 2004.

    Article  Google Scholar 

  72. Pelster, B., and W. W. Burggren. Central arterial hemodynamics in larval bullfrogs (Rana catesbeiana): developmental and seasonal influences. Am. J. Physiol. 260:R240–R246, 1991.

    Google Scholar 

  73. Pelster, B., and W. W. Burggren. Disruption of hemoglobin oxygen transport does not impact oxygen-dependent physiological processes in developing embryos of zebrafish (Danio rerio). Circ. Res. 79:358–362, 1996.

    Article  Google Scholar 

  74. Pelster, B., W. W. Burggren, S. Petrou, and I. Wahlqvist. Developmental changes in the acetylcholine influence on heart muscle of Rana catesbiana: In situ and in vitro effects. J. Exp. Zool. 267:1–8, 1993.

    Article  Google Scholar 

  75. Phoon, C. K. Circulatory physiology in the developing embryo. Curr. Opin. Pediatr. 13(5):456–464, 2001.

    Article  Google Scholar 

  76. Ratajska, A., and E. Czarnowska. Vasculogenesis of the embryonic heart: contribution of nucleated red blood cells to early vascular structures. Cardiovasc. Hematol. Disord.: Drug Targets 6(3):219–225, 2006.

    Article  Google Scholar 

  77. Rombough, P. J. Piscine cardiovascular development. In: Development of Cardiovascular Systems, edited by W. W. Burggren, and B. B. Keller. Cambridge: Cambridge University Press, 1997.

  78. Salvadori, M. L., T. B. Lessa, F. B. Russo, R. A. Fernandes, J. R. Kfoury, Jr., P. C. Braga, and M. A. Miglino. Mice embryology: a microscopic overview. Microsc. Res. Tech. 75(10):1437–1444, 2012.

    Article  Google Scholar 

  79. Schroeder, J. A., L. F. Jackson, D. C. Lee, and T. D. Camenisch. Form and function of developing heart valves: coordination by extracellular matrix and growth factor signaling. J. Mol. Med. (Berl). 81(7):392–403, 2003.

    Article  Google Scholar 

  80. Stainier, D. Y., and M. C. Fishman. Patterning the zebrafish heart tube: acquisition of anteroposterior polarity. Dev. Biol. 153(1):91–101, 1992.

    Article  Google Scholar 

  81. Stekelenburg-de Vos, S., P. Steendijk, N. T. Ursem, J. W. Wladimiroff, and R. E. Poelmann. Systolic and diastolic ventricular function in the normal and extra-embryonic venous clipped chicken embryo of stage 24: a pressure-volume loop assessment. Ultrasound Obstet. Gynecol. 30(3):325–331, 2007.

    Google Scholar 

  82. Strecker, R., T.-B. Seiler, H. Hollert, and T. Braunbeck. Oxygen requirements of zebrafish (Danio rerio) embryos in embryo toxicity testes with environmental samples. Comp. Biochem. Physiol. C: Toxicol. Pharm. 153:318–327, 2011.

    Google Scholar 

  83. Territo, P., and W. W. Burggren. Cardio-respiratory ontogeny during chronic carbon dioxide induced hypoxemia in the clawed frog Xenopus laevis. J. Exp. Biol. 201(9):1461–1472, 1998.

    Google Scholar 

  84. Territo, P., and W. W. Burggren. Cardio-respiratory ontogeny during chronic carbon monoxide induced hypoxemia in the clawed frog Xenopus laevis. J. Exp. Biol. 201:1461–1472, 1998.

    Google Scholar 

  85. Thornburg, K., S. Jonker, P. O’Tierney, N. Chattergoon, S. Louey, J. Faber, and G. Giraud. Regulation of the cardiomyocyte population in the developing heart. Prog. Biophys. Mol. Biol. 106(1):289–299, 2011.

    Article  Google Scholar 

  86. Thornburg, K. L., and M. S. Minette. Heart development and function before birth. Indian Pediatr. 35(5):409–413, 1998.

    Google Scholar 

  87. van Mierop, L. H. S. Localization of pacemaker in chick embryo heart at the time of initiation of heartbeat. Am. J. Physiol. 212:407–415, 1967.

    Google Scholar 

  88. Warburton, S. J., and R. Fritsche. Blood pressure control in a larval amphibian, Xenopus laevis. J. Exp. Biol. 203(13):2047–2052, 2000.

    Google Scholar 

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This study was supported by NSF operating grant IOS-1025823.

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Associate Editor Kerem Pekkan and Bradley B. Keller oversaw the review of this article.

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Burggren, W.W. Cardiovascular Development and Angiogenesis in the Early Vertebrate Embryo. Cardiovasc Eng Tech 4, 234–245 (2013). https://doi.org/10.1007/s13239-013-0118-x

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