Ligand-Dependent Notch Signaling in Vascular Formation

  • Tsutomu Kume

Abstract

The Notch signaling pathway is a critical component of vascular formation and morphogenesis in both development and disease. Compelling evidence indicates that Notch signaling is required for the induction of arterial-cell fate during development and for the selection of endothelial tip and stalk cells during sprouting angiogenesis. In mammals, two of the four Notch receptors (Notch1 and Notch4) and three of the five Notch ligands (Jagged1, Dll1 and Dll4) are predominantly expressed in vascular endothelial cells and are important for many aspects of vascular biology. During arterial cell-fate selection and angiogenesis, the roles of Notch1 and Notch4 are thought to be similar and the role of Dll4 is well-characterized. However, the molecular mechanisms that determine the functional similarities and differences of Notch ligands in vascular endothelial cells remain largely unknown; consequently, additional research is needed to elucidate the ligand-specific functions and mechanisms associated with Notch activation in the vascular endothelium. Results from recent studies indicate that Dll1 and Dll4 have distinct roles in the specification and maintenance of arterial cell identity, while Dll4 and Jagged1 have opposing effects on tip- and stalk-cell selection during sprouting angiogenesis. This chapter will focus on the newly discovered, distinct roles of several Notch ligands in the regulation of blood vessel formation and will provide perspectives for future research in the field.

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References

  1. 1.
    Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006; 7(9):678–689.PubMedCrossRefGoogle Scholar
  2. 2.
    Alva JA, Iruela-Arispe ML. Notch signaling in vascular morphogenesis. Curr Opin Hematol 2004; 11(4):278–283.PubMedCrossRefGoogle Scholar
  3. 3.
    Gridley T. Notch signaling in vascular development and physiology. Development 2007; 134(15):2709–2718.PubMedCrossRefGoogle Scholar
  4. 4.
    Hofmann JJ, Iruela-Arispe ML. Notch signaling in blood vessels: who is talking to whom about what? Circ Res 2007; 100(11):1556–1568.PubMedCrossRefGoogle Scholar
  5. 5.
    Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell 2009; 16(2):196–208.PubMedCrossRefGoogle Scholar
  6. 6.
    Roca C, Adams RH. Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 15 2007;21(20):2511–2524.CrossRefGoogle Scholar
  7. 7.
    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):489–497.PubMedGoogle Scholar
  8. 8.
    Komatsu H, Chao MY, Larkins-Ford J et al. OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development. PLoS Biol 2008; 6(8):e196.PubMedCrossRefGoogle Scholar
  9. 9.
    Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137(2):216–233.PubMedCrossRefGoogle Scholar
  10. 10.
    Fiuza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol 2007; 194(3):459–474.PubMedCrossRefGoogle Scholar
  11. 11.
    Zolkiewska A. ADAM proteases: ligand processing and modulation of the Notch pathway. Cell Mol Life Sci 2008; 65(13):2056–2068.PubMedCrossRefGoogle Scholar
  12. 12.
    D’souza B, Miyamoto A, Weinmaster G. The many facets of Notch ligands. Oncogene 2008; 27(38):5148–5167.PubMedCrossRefGoogle Scholar
  13. 13.
    Krebs LT, Xue Y, Norton CR et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 2000; 14(11):1343-1352.Google Scholar
  14. 14.
    Wu J, Bresnick EH. Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation. Mol Cell Biol 2007; 27(6):2411–2422.PubMedCrossRefGoogle Scholar
  15. 15.
    Wu J, Iwata F, Grass JA et al. Molecular determinants of NOTCH4 transcription in vascular endothelium. Mol Cell Biol 2005; 25(4):1458–1474.PubMedCrossRefGoogle Scholar
  16. 16.
    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
  17. 17.
    Wu J, Bresnick EH. Bare rudiments of notch signaling: how receptor levels are regulated. Trends Biochem Sci 2007; 32(10):477–485.PubMedCrossRefGoogle Scholar
  18. 18.
    Beckers J, Clark A, Wunsch K et al. Expression of the mouse Delta1 gene during organogenesis and fetal development. Mech Dev 1999; 84(1-2):165–168.PubMedCrossRefGoogle Scholar
  19. 19.
    Sorensen I, Adams RH, Gossler A. DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood 2009; 113(22):5680–5688.PubMedCrossRefGoogle Scholar
  20. 20.
    Villa N, Walker L, Lindsell CE et al. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 2001; 108(1-2):161–164.PubMedCrossRefGoogle Scholar
  21. 21.
    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):466–475.PubMedCrossRefGoogle Scholar
  22. 22.
    Hayashi H, Kume T. Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells. PLoS ONE 2008; 3(6):e2401.PubMedCrossRefGoogle Scholar
  23. 23.
    Hellstrom M, Phng LK, Hofmann JJ et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 2007; 445(7129):776–780.PubMedCrossRefGoogle Scholar
  24. 24.
    Liu ZJ, Shirakawa T, Li Y et al. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 2003; 23(1):14–25.PubMedCrossRefGoogle Scholar
  25. 25.
    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):3219–3224.PubMedCrossRefGoogle Scholar
  26. 26.
    Patel NS, Li JL, Generali D et al. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 2005; 65(19):8690–8697.PubMedCrossRefGoogle Scholar
  27. 27.
    Seo S, Fujita H, Nakano A et al. The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev Biol 2006; 294(2):458–470.PubMedCrossRefGoogle Scholar
  28. 28.
    Williams CK, Li JL, Murga M et al. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 2006; 107(3):931–939.PubMedCrossRefGoogle Scholar
  29. 29.
    Lawson ND, Scheer N, Pham VN et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 2001; 128(19):3675–3683.PubMedGoogle Scholar
  30. 30.
    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):127–136.PubMedCrossRefGoogle Scholar
  31. 31.
    Limbourg FP, Takeshita K, Radtke F et al. Essential role of endothelial Notch1 in angiogenesis. Circulation 2005; 111(14):1826–1832.PubMedCrossRefGoogle Scholar
  32. 32.
    Takeshita K, Satoh M, Ii M et al. Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circ Res 2007; 100(1):70–78.PubMedCrossRefGoogle Scholar
  33. 33.
    Uyttendaele H, Ho J, Rossant J et al. Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci USA 2001; 98(10):5643–5648.PubMedCrossRefGoogle Scholar
  34. 34.
    Carlson TR, Yan Y, Wu X et al. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci USA 2005; 102(28):9884–9889.PubMedCrossRefGoogle Scholar
  35. 35.
    Duarte A, Hirashima M, Benedito R et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 2004; 18(20):2474–2478.PubMedCrossRefGoogle Scholar
  36. 36.
    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):15949–15954.PubMedCrossRefGoogle Scholar
  37. 37.
    Krebs LT, Shutter JR, Tanigaki K et al. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 2004; 18(20):2469–2473.PubMedCrossRefGoogle Scholar
  38. 38.
    Limbourg A, Ploom M, Elligsen D et al. Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res 2007; 100(3):363–371.PubMedCrossRefGoogle Scholar
  39. 39.
    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):707–710.PubMedCrossRefGoogle Scholar
  40. 40.
    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):2730–2735.CrossRefGoogle Scholar
  41. 41.
    High FA, Lu MM, Pear WS et al. Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci USA 2008; 105(6):1955–1959.PubMedCrossRefGoogle Scholar
  42. 42.
    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):1886–1895.PubMedCrossRefGoogle Scholar
  43. 43.
    Campos AH, Wang W, Pollman MJ et al. Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ Res 2002; 91(11):999–1006.PubMedCrossRefGoogle Scholar
  44. 44.
    Leslie JD, Ariza-McNaughton L, Bermange AL et al. Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 2007; 134(5):839–844.PubMedCrossRefGoogle Scholar
  45. 45.
    Noguera-Troise I, Daly C, Papadopoulos NJ et al. Blockade of Dll4 inhibits tumour growth by promoting nonproductive angiogenesis. Nature 2006; 444(7122):1032–1037.PubMedCrossRefGoogle Scholar
  46. 46.
    Ridgway J, Zhang G, Wu Y et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 2006; 444(7122):1083–1087.PubMedCrossRefGoogle Scholar
  47. 47.
    Sainson RC, Aoto J, Nakatsu MN et al. Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 2005; 19(8):1027–1029.PubMedGoogle Scholar
  48. 48.
    Siekmann AF, Lawson ND. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 2007; 445(7129):781–784.PubMedCrossRefGoogle Scholar
  49. 49.
    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):3225–3230.PubMedCrossRefGoogle Scholar
  50. 50.
    Benedito R, Roca C, Sorensen I et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 2009; 137(6):1124–1135.PubMedCrossRefGoogle Scholar
  51. 51.
    Hainaud P, Contreres JO, Villemain A et al. The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res 2006; 66(17):8501–8510.PubMedCrossRefGoogle Scholar
  52. 52.
    Mailhos C, Modlich U, Lewis J et al. Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 2001; 69(2-3):135–144.PubMedCrossRefGoogle Scholar
  53. 53.
    Scehnet JS, Jiang W, Kumar SR et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 2007; 109(11):4753–4760.PubMedCrossRefGoogle Scholar
  54. 54.
    Li JL, Sainson RC, Shi W et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function and promotes tumor growth in vivo. Cancer Res 2007; 67(23):11244–11253.PubMedCrossRefGoogle Scholar
  55. 55.
    Thurston G, Noguera-Troise I, Yancopoulos GD. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 2007; 7(5):327–331.PubMedCrossRefGoogle Scholar
  56. 56.
    Zeng Q, Li S, Chepeha DB et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 2005; 8(1):13–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Dufraine J, Funahashi Y, Kitajewski J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 2008; 27(38):5132–5137.PubMedCrossRefGoogle Scholar
  58. 58.
    Funahashi Y, Hernandez SL, Das I et al. A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth and angiogenesis. Cancer Res 2008; 68(12):4727–4735.PubMedCrossRefGoogle Scholar
  59. 59.
    Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008; 28(9):1584–1595.PubMedCrossRefGoogle Scholar
  60. 60.
    Kawamoto A, Losordo DW. Endothelial progenitor cells for cardiovascular regeneration. Trends Cardiovasc Med 2008; 18(1):33–37.PubMedCrossRefGoogle Scholar
  61. 61.
    Prater DN, Case J, Ingram DA et al. Working hypothesis to redefine endothelial progenitor cells. Leukemia 2007; 21(6):1141–1149.PubMedCrossRefGoogle Scholar
  62. 62.
    Kwon SM, Alev C, Asahara T. The role of notch signaling in endothelial progenitor cell biology. Trends Cardiovasc Med 2009; 19(5):170–173.PubMedCrossRefGoogle Scholar
  63. 63.
    Kwon SM, Eguchi M, Wada M et al. Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization. Circulation 2008; 118(2):157–165.PubMedCrossRefGoogle Scholar
  64. 64.
    Ii M, Takeshita K, Ibusuki K et al. Notch Signaling Regulates Endothelial Progenitor Cell Activity During Recovery From Arterial Injury in Hypercholesterolemic Mice. Circulation 121(9):1104–1112.Google Scholar
  65. 65.
    Miyamoto A, Lau R, Hein PW et al. Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation. J Biol Chem 2006; 281(15):10089–10097.PubMedCrossRefGoogle Scholar
  66. 66.
    Nehring LC, Miyamoto A, Hein PW et al. The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface. J Biol Chem 2005; 280(21):20349–20355.PubMedCrossRefGoogle Scholar
  67. 67.
    Albig AR, Becenti DJ, Roy TG et al. Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells. Microvasc Res 2008; 76(1):7–14.PubMedCrossRefGoogle Scholar
  68. 68.
    Albig AR, Roy TG, Becenti DJ et al. Transcriptome analysis of endothelial cell gene expression induced by growth on matrigel matrices: identification and characterization of MAGP-2 and lumican as novel regulators of angiogenesis. Angiogenesis 2007; 10(3):197–216.PubMedCrossRefGoogle Scholar
  69. 69.
    Hoey T, Yen WC, Axelrod F et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 2009; 5(2):168–177.PubMedCrossRefGoogle Scholar
  70. 70.
    Kume T. Novel insights into the differential functions of Notch ligands in vascular formation. J Angiogenes Res 2009; 1:8.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Tsutomu Kume
    • 1
  1. 1.Feinberg Cardiovascular Research Institute, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

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