Notch Signaling in Vascular Development

  • Shalini Jadeja
  • Marcus Fruttiger


Notch signaling is a very widespread signaling system that has diverse functions in many developmental systems in an evolutionarily conserved manner. Notch signaling is known to play a role in regulating epithelial, neuronal, hematopoietic, and muscle cell fate, and in the last decade, the role played by Notch signaling in the vasculature has been uncovered.

In this chapter, we will discuss the development of hematopoietic and vascular cells from cell precursors to a differentiated and fully functional vascular system, along with the role of various Notch signaling molecules in defining the different cell types that make up this system. Notch ligands and receptors are expressed in the developing vasculature and blood cells from the early emergence of hemangioblast precursors through to differentiated vascular beds. The characteristic Notch signaling mechanisms of lateral inhibition and lateral induction enable neighboring cells to create the diversity in cell types required to form not only the blood vessels, but also the vessel wall and thereby utilizing a relatively small number of genes to control multiple processes.


Notch Signaling Notch Receptor Primitive Streak Notch Ligand Dorsal Aorta 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Kinder SJ, Tsang TE, Wakamiya M, et al. The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm. Development. 2001;128(18):3623–34.PubMedGoogle Scholar
  2. 2.
    Lawson KA, Meneses JJ, Pedersen RA. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development. 1991;113(3):891–911.PubMedGoogle Scholar
  3. 3.
    Baron MH. Embryonic origins of mammalian hematopoiesis. Exp Hematol. 2003;31(12):1160–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Ferkowicz MJ, Starr M, Xie X, et al. CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo. Development. 2003;130(18):4393–403.PubMedCrossRefGoogle Scholar
  5. 5.
    Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development. 1998;125(4):725–32.PubMedGoogle Scholar
  6. 6.
    Sabin F. Studies on the origin of blood vessels and of red blood corpuscles as seen in the living blastoderm of chicks during the second day of incubation. Contrib Embryol Carnegie Inst Wash. 1920;9:214–62.Google Scholar
  7. 7.
    Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature. 2004;432(7017):625–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535):62–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Kinder SJ, Tsang TE, Quinlan GA, Hadjantonakis AK, Nagy A, Tam PP. The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo. Development. 1999;126(21):4691–701.PubMedGoogle Scholar
  10. 10.
    Kattman SJ, Huber TL, Keller GM. Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell. 2006;11(5):723–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Yamashita J, Itoh H, Hirashima M, et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature. 2000;408(6808):92–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Ema M, Rossant J. Cell fate decisions in early blood vessel formation. Trends Cardiovasc Med. 2003;13(6):254–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Furuta C, Ema H, Takayanagi S, et al. Discordant developmental waves of angioblasts and hemangioblasts in the early gastrulating mouse embryo. Development. 2006;133(14):2771–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Risau W, Flamme I. Vasculogenesis. Annu Rev Cell Dev Biol. 1995;11:73–91.PubMedCrossRefGoogle Scholar
  15. 15.
    Poole TJ, Coffin JD. Vasculogenesis and angiogenesis: two distinct morphogenetic mechanisms establish embryonic vascular pattern. J Exp Zool. 1989;251(2):224–31.PubMedCrossRefGoogle Scholar
  16. 16.
    Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–33.PubMedCrossRefGoogle Scholar
  18. 18.
    Talora C, Campese AF, Bellavia D, et al. Notch signaling and diseases: an evolutionary journey from a simple beginning to complex outcomes. Biochim Biophys Acta. 2008;1782(9):489–97.PubMedGoogle Scholar
  19. 19.
    Sanalkumar R, Dhanesh SB, James J. Non-canonical activation of Notch signaling/target genes in vertebrates. Cell Mol Life Sci. 2010;67(17):2957–68.PubMedCrossRefGoogle Scholar
  20. 20.
    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Bray S. Notch signalling in Drosophila: three ways to use a pathway. Semin Cell Dev Biol. 1998;9(6):591–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678–89.PubMedCrossRefGoogle Scholar
  23. 23.
    Fortini ME. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell. 2009;16(5):633–47.PubMedCrossRefGoogle Scholar
  24. 24.
    D’Souza B, Miyamoto A, Weinmaster G. The many facets of Notch ligands. Oncogene. 2008;27(38):5148–67.PubMedCrossRefGoogle Scholar
  25. 25.
    Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G. Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol Biol Cell. 2005;16(2):927–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Haines N, Irvine KD. Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol. 2003;4(10):786–97.PubMedGoogle Scholar
  27. 27.
    Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development. 1996;122(7):2251–9.PubMedGoogle Scholar
  28. 28.
    Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T. Notch1 is essential for postimplantation development in mice. Genes Dev. 1994;8(6):707–19.PubMedCrossRefGoogle Scholar
  29. 29.
    Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK. Essential role of endothelial Notch1 in angiogenesis. Circulation. 2005;111(14):1826–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Krebs LT, Xue Y, Norton CR, et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 2000;14(11):1343–52.PubMedGoogle Scholar
  31. 31.
    Uyttendaele H, Ho J, Rossant J, Kitajewski J. Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci USA. 2001;98(10):5643–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Murphy PA, Lam MT, Wu X, et al. Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proc Natl Acad Sci USA. 2008;105(31):10901–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Alva JA, Iruela-Arispe ML. Notch signaling in vascular morphogenesis. Curr Opin Hematol. 2004;11(4):278–83.PubMedCrossRefGoogle Scholar
  34. 34.
    Claxton S, Fruttiger M. Periodic Delta-like 4 expression in developing retinal arteries. Gene Expr Patterns. 2004;5(1):123–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev. 2001;108(1–2):161–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Joutel A, Andreux F, Gaulis S, et al. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest. 2000;105(5):597–605.PubMedCrossRefGoogle Scholar
  37. 37.
    Krebs LT, Xue Y, Norton CR, et al. Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis. 2003;37(3):139–43.PubMedCrossRefGoogle Scholar
  38. 38.
    Domenga V, Fardoux P, Lacombe P, et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 2004;18(22):2730–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Beckers J, Clark A, Wunsch K, De Hrabe AM, Gossler A. Expression of the mouse Delta1 gene during organogenesis and fetal development. Mech Dev. 1999;84(1–2):165–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Limbourg A, Ploom M, Elligsen D, et al. Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res. 2007;100(3):363–71.PubMedCrossRefGoogle Scholar
  41. 41.
    Shutter JR, Scully S, Fan W, et al. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev. 2000;14(11):1313–8.PubMedGoogle Scholar
  42. 42.
    De Hrabe AM, McIntyre J, Gossler A. Maintenance of somite borders in mice requires the Delta homologue DII1. Nature. 1997;386(6626):717–21.CrossRefGoogle Scholar
  43. 43.
    Duarte A, Hirashima M, Benedito R, et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 2004;18(20):2474–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Gale NW, Dominguez MG, Noguera I, et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA. 2004;101(45):15949–54.PubMedCrossRefGoogle Scholar
  45. 45.
    Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 2004;18(20):2469–73.PubMedCrossRefGoogle Scholar
  46. 46.
    Hellstrom M, Phng LK, Hofmann JJ, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007;445(7129):776–80.PubMedCrossRefGoogle Scholar
  47. 47.
    Suchting S, Freitas C, le Noble F, et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA. 2007;104(9):3225–30.PubMedCrossRefGoogle Scholar
  48. 48.
    Lobov IB, Renard RA, Papadopoulos N, et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA. 2007;104(9):3219–24.PubMedCrossRefGoogle Scholar
  49. 49.
    Irvin DK, Nakano I, Paucar A, Kornblum HI. Patterns of Jagged1, Jagged2, Delta-like 1 and Delta-like 3 expression during late embryonic and postnatal brain development suggest multiple functional roles in progenitors and differentiated cells. J Neurosci Res. 2004;75(3):330–43.PubMedCrossRefGoogle Scholar
  50. 50.
    Loomes KM, Underkoffler LA, Morabito J, et al. The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome. Hum Mol Genet. 1999;8(13):2443–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Xue Y, Gao X, Lindsell CE, et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet. 1999;8(5):723–30.PubMedCrossRefGoogle Scholar
  52. 52.
    High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA. Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci USA. 2008;105(6):1955–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Jiang R, Lan Y, Chapman HD, et al. Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev. 1998;12(7):1046–57.PubMedCrossRefGoogle Scholar
  54. 54.
    Lee CY, Vogeli KM, Kim SH, et al. Notch signaling functions as a cell-fate switch between the endothelial and hematopoietic lineages. Curr Biol. 2009;19(19):1616–22.PubMedCrossRefGoogle Scholar
  55. 55.
    Sheng G. Primitive and definitive erythropoiesis in the yolk sac: a bird’s eye view. Int J Dev Biol. 2010;54(6–7):1033–43.PubMedCrossRefGoogle Scholar
  56. 56.
    Taoudi S, Medvinsky A. Functional identification of the hematopoietic stem cell niche in the ventral domain of the embryonic dorsal aorta. Proc Natl Acad Sci USA. 2007;104(22):9399–403.PubMedCrossRefGoogle Scholar
  57. 57.
    Medvinsky A, Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell. 1996;86(6):897–906.PubMedCrossRefGoogle Scholar
  58. 58.
    Garcia-Porrero JA, Godin IE, Dieterlen-Lievre F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat Embryol (Berl). 1995;192(5):425–35.CrossRefGoogle Scholar
  59. 59.
    Kumano K, Chiba S, Kunisato A, et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity. 2003;18(5):699–711.PubMedCrossRefGoogle Scholar
  60. 60.
    Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A. RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development. 2005;132(5):1117–26.PubMedCrossRefGoogle Scholar
  61. 61.
    Robert-Moreno A, Guiu J, Ruiz-Herguido C, et al. Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO J. 2008;27(13):1886–95.PubMedCrossRefGoogle Scholar
  62. 62.
    Radtke F, Fasnacht N, Macdonald HR. Notch signaling in the immune system. Immunity. 2010;32(1):14–27.PubMedCrossRefGoogle Scholar
  63. 63.
    Yuan JS, Kousis PC, Suliman S, Visan I, Guidos CJ. Functions of notch signaling in the immune system: consensus and controversies. Annu Rev Immunol. 2010;28:343–65.PubMedCrossRefGoogle Scholar
  64. 64.
    Majesky MW. Developmental basis of vascular smooth muscle diversity. Arterioscler Thromb Vasc Biol. 2007;27(6):1248–58.PubMedCrossRefGoogle Scholar
  65. 65.
    Shin M, Nagai H, Sheng G. Notch mediates Wnt and BMP signals in the early separation of smooth muscle progenitors and blood/endothelial common progenitors. Development. 2009;136(4):595–603.PubMedCrossRefGoogle Scholar
  66. 66.
    Schroeder T, Meier-Stiegen F, Schwanbeck R, et al. Activated Notch1 alters differentiation of embryonic stem cells into mesodermal cell lineages at multiple stages of development. Mech Dev. 2006;123(7):570–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383(6602):707–10.PubMedCrossRefGoogle Scholar
  68. 68.
    Liu H, Kennard S, Lilly B. NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res. 2009;104(4):466–75.PubMedCrossRefGoogle Scholar
  69. 69.
    Doi H, Iso T, Sato H, et al. Jagged1-selective notch signaling induces smooth muscle differentiation via a RBP-Jkappa-dependent pathway. J Biol Chem. 2006;281(39):28555–64.PubMedCrossRefGoogle Scholar
  70. 70.
    Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell. 1998;93(5):741–53.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhong TP, Childs S, Leu JP, Fishman MC. Gridlock signalling pathway fashions the first embryonic artery. Nature. 2001;414(6860):216–20.PubMedCrossRefGoogle Scholar
  72. 72.
    Lawson ND, Vogel AM, Weinstein BM. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell. 2002;3(1):127–36.PubMedCrossRefGoogle Scholar
  73. 73.
    Lawson ND, Scheer N, Pham VN, et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development. 2001;128(19):3675–83.PubMedGoogle Scholar
  74. 74.
    Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. Gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science. 2000;287(5459):1820–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Trindade A, Kumar SR, Scehnet JS, et al. Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos. Blood. 2008;112(5):1720–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Benedito R, Trindade A, Hirashima M, et al. Loss of Notch signalling induced by Dll4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli. BMC Dev Biol. 2008;8:117.PubMedCrossRefGoogle Scholar
  77. 77.
    Kim YH, Hu H, Guevara-Gallardo S, Lam MT, Fong SY, Wang RA. Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis. Development. 2008;135(22):3755–64.PubMedCrossRefGoogle Scholar
  78. 78.
    Sorensen I, Adams RH, Gossler A. DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood. 2009;113(22):5680–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Fruttiger M. Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Invest Ophthalmol Vis Sci. 2002;43(2):522–7.PubMedGoogle Scholar
  80. 80.
    Fruttiger M. Development of the retinal vasculature. Angiogenesis. 2007;10(2):77–88.PubMedCrossRefGoogle Scholar
  81. 81.
    Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161(6):1163–77.PubMedCrossRefGoogle Scholar
  82. 82.
    Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell. 2009;16(2):196–208.PubMedCrossRefGoogle Scholar
  83. 83.
    Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J. Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development. 2007;134(5):839–44.PubMedCrossRefGoogle Scholar
  84. 84.
    Siekmann AF, Lawson ND. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature. 2007;445(7129):781–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Benedito R, Roca C, Sorensen I, et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell. 2009;137(6):1124–35.PubMedCrossRefGoogle Scholar
  86. 86.
    Holderfield MT, Hughes CC. Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-beta in vascular morphogenesis. Circ Res. 2008;102(6):637–52.PubMedCrossRefGoogle Scholar
  87. 87.
    Franco CA, Liebner S, Gerhardt H. Vascular morphogenesis: a Wnt for every vessel? Curr Opin Genet Dev. 2009;19(5):476–83.PubMedCrossRefGoogle Scholar
  88. 88.
    Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16(3):235–42.PubMedCrossRefGoogle Scholar

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© Springer-Verlag London Limited 2012

Authors and Affiliations

  1. 1.Medical and Developmental Genetics, MRC Human Genetics UnitWestern General HospitalEdinburghUK
  2. 2.Cell BiologyUCL Institute of OphthalmologyLondonUK

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