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Endothelial Ontogeny During Embryogenesis: Role of Cytokine Signaling Pathways

  • Chapter
Regulatory Networks in Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

Efficient distribution of oxygen and nutrients are fundamental and universal requirements of tissue homeostasis. In adults, angiogenesis from existing vessels occurs during routine tissue repair and is a prerequisite for the advance of tumor growth. Indeed, proliferation of any solid tissue beyond microscopic scales, in vivo or in vitro, is inherently dependent on vascularization. Endothelial ontogeny is hugely relevant to clinical science, as millions of patients each year succumb to vascular diseases resulting in mortality and morbidity due to tissue ischemia. Medical interventions are only partially effective in revascularizing ischemic tissues; moreover, recent clinical trials to induce revascularization using adult marrow-derived stem cells have yielded only minor benefit. Human embryonic stem cells (ESCs) have the potential to provide an unlimited source of vascular tissue for cell-based therapies, while also providing insight into the molecular events underlying human vascular development. In order for human ESCs to fulfill this potential, however, it will first be necessary to define the developmental events that influence endothelial differentiation and blood vessel formation. The molecular pathways involved in developmental vasculogenesis in mouse have been well studied, yet many elements of this process are obscure, and the correlation of these studies to human biology remains to be seen. Below, we review the current understanding of mammalian vascular development gained from studies of mouse genetic models and ESCs, focusing on the cytokine-mediated signaling pathways that govern this process.

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References

  1. Baron MH. Molecular regulation of embryonic hematopoiesis and vascular development: a novel pathway. J Hematother Stem Cell Res. 2001;10:587–94.

    Article  PubMed  CAS  Google Scholar 

  2. Matsumoto K, Yoshitomi H, Rossant J, Zaret KS. Liver organogenesis promoted by endothelial cells prior to vascular function. Science. 2001;294:559–63.

    Article  PubMed  CAS  Google Scholar 

  3. Lammert E, Cleaver O, Melton D. Role of endothelial cells in early pancreas and liver development. Mech Dev. 2003;120:59–64.

    Article  PubMed  CAS  Google Scholar 

  4. Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003;9:702–12.

    Article  PubMed  CAS  Google Scholar 

  5. Smith AG. Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol. 2001;17:435–62.

    Article  PubMed  CAS  Google Scholar 

  6. Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 2006;312:549–60.

    Article  PubMed  CAS  Google Scholar 

  7. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991;5:1806–14.

    Article  PubMed  CAS  Google Scholar 

  8. Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell. 1993;4:1317–26.

    PubMed  CAS  Google Scholar 

  9. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–9.

    Article  PubMed  CAS  Google Scholar 

  10. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–42.

    Article  PubMed  CAS  Google Scholar 

  11. Ruhrberg C, Gerhardt H, Golding M, et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 2002;16: 2684–98.

    Article  PubMed  CAS  Google Scholar 

  12. Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161:1163–77.

    Article  PubMed  CAS  Google Scholar 

  13. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A. 1998;95: 9349–54.

    Article  PubMed  CAS  Google Scholar 

  14. Kearney JB, Ambler CA, Monaco KA, Johnson N, Rapoport RG, Bautch VL. Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division. Blood. 2002;99: 2397–407.

    Article  PubMed  CAS  Google Scholar 

  15. Fong GH, Zhang L, Bryce DM, Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development. 1999;126:3015–25.

    PubMed  CAS  Google Scholar 

  16. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376:62–6.

    Article  PubMed  CAS  Google Scholar 

  17. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE. 2001;2001:RE21.

    Article  PubMed  CAS  Google Scholar 

  18. Rafii S. Circulating endothelial precursors: mystery, reality, and promise. J Clin Invest. 2000;105:17–9.

    Article  PubMed  CAS  Google Scholar 

  19. Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000;95:952–8.

    PubMed  CAS  Google Scholar 

  20. Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001;193:1005–14.

    Article  PubMed  CAS  Google Scholar 

  21. Young PP, Hofling AA, Sands MS. VEGF increases engraftment of bone marrow-derived endothelial progenitor cells (EPCs) into vasculature of newborn murine recipients. Proc Natl Acad Sci U S A. 2002;99:11951–6.

    Article  PubMed  CAS  Google Scholar 

  22. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–37.

    Article  PubMed  CAS  Google Scholar 

  23. Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006;313:1785–7.

    Article  PubMed  CAS  Google Scholar 

  24. Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001;7: 1194–201.

    Article  PubMed  CAS  Google Scholar 

  25. Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309.

    Article  PubMed  CAS  Google Scholar 

  26. Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–9.

    Article  PubMed  CAS  Google Scholar 

  27. De Robertis EM, Kuroda H. Dorsal-ventral patterning and neural induction in Xenopus embryos. Annu Rev Cell Dev Biol. 2004;20:285–308.

    Article  PubMed  Google Scholar 

  28. Marshall CJ, Kinnon C, Thrasher AJ. Polarized expression of bone morphogenetic protein-4 in the human aorta-gonad-mesonephros region. Blood. 2000;96:1591–3.

    PubMed  CAS  Google Scholar 

  29. Winnier G, Blessing M, Labosky PA, Hogan BL. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 1995;9:2105–16.

    Article  PubMed  CAS  Google Scholar 

  30. Gu Z, Reynolds EM, Song J, et al. The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo. Development. 1999;126:2551–61.

    PubMed  CAS  Google Scholar 

  31. Mishina Y, Suzuki A, Ueno N, Behringer RR. Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev. 1995;9: 3027–37.

    Article  PubMed  CAS  Google Scholar 

  32. Tremblay KD, Dunn NR, Robertson EJ. Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation. Development. 2001;128:3609–21.

    PubMed  CAS  Google Scholar 

  33. Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk MM, Zwijsen A. Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development. 1999;126:1631–42.

    PubMed  CAS  Google Scholar 

  34. Park C, Afrikanova I, Chung YS, et al. A hierarchical order of factors in the generation of FLK1- and SCL-expressing hematopoietic and endothelial progenitors from embryonic stem cells. Development. 2004;131:2749–62.

    Article  PubMed  CAS  Google Scholar 

  35. Valdimarsdottir G, Goumans MJ, Rosendahl A, et al. Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation. 2002;106:2263–70.

    Article  PubMed  CAS  Google Scholar 

  36. Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res. 2006;98:209–17.

    Article  PubMed  CAS  Google Scholar 

  37. Raida M, Heymann AC, Gunther C, Niederwieser D. Role of bone morphogenetic protein 2 in the crosstalk between endothelial progenitor cells and mesenchymal stem cells. Int J Mol Med. 2006;18:735–9.

    PubMed  CAS  Google Scholar 

  38. Liu D, Wang J, Kinzel B, et al. Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity. Blood. 2007;110:1502–10.

    Article  PubMed  CAS  Google Scholar 

  39. Kimelman D. Mesoderm induction: from caps to chips. Nat Rev Genet. 2006;7:360–72.

    Article  PubMed  CAS  Google Scholar 

  40. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development. 1995;121:1845–54.

    PubMed  CAS  Google Scholar 

  41. Goumans MJ, Zwijsen A, van Rooijen MA, Huylebroeck D, Roelen BA, Mummery CL. Transforming growth factor-beta signalling in extraembryonic mesoderm is required for yolk sac vasculogenesis in mice. Development. 1999;126:3473–83.

    PubMed  CAS  Google Scholar 

  42. Larsson J, Goumans MJ, Sjostrand LJ, et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J. 2001;20:1663–73.

    Article  PubMed  CAS  Google Scholar 

  43. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002;21: 1743–53.

    Article  PubMed  CAS  Google Scholar 

  44. Lebrin F, Deckers M, Bertolino P, Ten Dijke P. TGF-beta receptor function in the endothelium. Cardiovasc Res. 2005;65:599–608.

    Article  PubMed  CAS  Google Scholar 

  45. Arthur HM, Ure J, Smith AJ, et al. Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol. 2000;217:42–53.

    Article  PubMed  CAS  Google Scholar 

  46. Goumans MJ, Mummery C. Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Int J Dev Biol. 2000;44:253–65.

    PubMed  CAS  Google Scholar 

  47. Oshima M, Oshima H, Taketo MM. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol. 1996;179:297–302.

    Article  PubMed  CAS  Google Scholar 

  48. Oh SP, Seki T, Goss KA, et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000;97:2626–31.

    Article  PubMed  CAS  Google Scholar 

  49. Wang H, Charles PC, Wu Y, et al. Gene expression profile signatures indicate a role for Wnt signaling in endothelial commitment from embryonic stem cells. Circ Res. 2006;98:1331–9.

    Article  PubMed  CAS  Google Scholar 

  50. Naito AT, Shiojima I, Akazawa H, et al. Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci U S A. 2006;103:19812–7.

    Article  PubMed  CAS  Google Scholar 

  51. Gale NW, Yancopoulos GD. Ephrins and their receptors: a repulsive topic? Cell Tissue Res. 1997;290:227–41.

    Article  PubMed  CAS  Google Scholar 

  52. Zhang J, Hughes S. Role of the ephrin and Eph receptor tyrosine kinase families in angiogenesis and development of the cardiovascular system. J Pathol. 2006;208:453–61.

    Article  PubMed  CAS  Google Scholar 

  53. Gerety SS, Anderson DJ. Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development. 2002;129: 1397–410.

    PubMed  CAS  Google Scholar 

  54. Adams RH, Wilkinson GA, Weiss C, et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 1999;13:295–306.

    Article  PubMed  CAS  Google Scholar 

  55. 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;93:741–53.

    Article  PubMed  CAS  Google Scholar 

  56. Maekawa H, Oike Y, Kanda S, et al. Ephrin-B2 induces migration of endothelial cells through the phosphatidylinositol-3 kinase pathway and promotes angiogenesis in adult vasculature. Arterioscler Thromb Vasc Biol. 2003;23:2008–14.

    Article  PubMed  CAS  Google Scholar 

  57. Fuller T, Korff T, Kilian A, Dandekar G, Augustin HG. Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci. 2003;116:2461–70.

    Article  PubMed  Google Scholar 

  58. Wang Z, Cohen K, Shao Y, Mole P, Dombkowski D, Scadden DT. Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, and blood vessels. Blood. 2004;103:100–9.

    Article  PubMed  CAS  Google Scholar 

  59. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770–6.

    Article  PubMed  CAS  Google Scholar 

  60. Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T. Notch1 is essential for postimplantation development in mice. Genes Dev. 1994;8:707–19.

    Article  PubMed  CAS  Google Scholar 

  61. Krebs LT, Xue Y, Norton CR, et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 2000;14:1343–52.

    PubMed  CAS  Google Scholar 

  62. Xue Y, Gao X, Lindsell CE, et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet. 1999;8:723–30.

    Article  PubMed  CAS  Google Scholar 

  63. Duarte A, Hirashima M, Benedito R, et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 2004;18:2474–8.

    Article  PubMed  CAS  Google Scholar 

  64. 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 U S A. 2004;101:15949–54.

    Article  PubMed  CAS  Google Scholar 

  65. Betsholtz C, Karlsson L, Lindahl P. Developmental roles of platelet-derived growth factors. Bioessays. 2001;23:494–507.

    Article  PubMed  CAS  Google Scholar 

  66. Leveen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 1994;8:1875–87.

    Article  PubMed  CAS  Google Scholar 

  67. Soriano P. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev. 1994;8: 1888–96.

    Article  PubMed  CAS  Google Scholar 

  68. Varjosalo M, Taipale J. Hedgehog signaling. J Cell Sci. 2007;120:3–6.

    Article  PubMed  CAS  Google Scholar 

  69. Byrd N, Grabel L. Hedgehog signaling in murine vasculogenesis and angiogenesis. Trends Cardiovasc Med. 2004;14:308–13.

    Article  PubMed  CAS  Google Scholar 

  70. Byrd N, Becker S, Maye P, et al. Hedgehog is required for murine yolk sac angiogenesis. Development. 2002;129: 361–72.

    PubMed  CAS  Google Scholar 

  71. Zhang XM, Ramalho-Santos M, McMahon AP. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell. 2001;106:781–92.

    Article  PubMed  CAS  Google Scholar 

  72. Petit I, Karajannis MA, Vincent L, et al. The microtubule targeting agent, CA4P, regresses leukemic xenografts by disrupting interaction with vascular vells and mitochondrial-dependent cell death. Blood. 2008;111(4):1951–61.

    Article  PubMed  CAS  Google Scholar 

  73. Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature. 1998;393:591–4.

    Article  PubMed  CAS  Google Scholar 

  74. Shepherd RM, Capoccia BJ, Devine SM, et al. Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100. Blood.. 2006;108: 3662–7.

    Article  PubMed  CAS  Google Scholar 

  75. Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.

    Article  PubMed  CAS  Google Scholar 

  76. Yamaguchi J, Kusano KF, Masuo O, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation. 2003;107:1322–8.

    Article  PubMed  CAS  Google Scholar 

  77. Walter DH, Haendeler J, Reinhold J, et al. Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease. Circ Res. 2005;97:1142–51.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Ansary Center for Stem Cell Therapeutics, Department of Genetic Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, 1300 York Avenue, Room A-863, 10021, New York, NY

    Daylon James & Shahin Rafii

  2. Department of Medicine/Medical Oncology, Box 8, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, 10065, New York, NY

    Marco Seandel

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  1. Daylon James
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  2. Marco Seandel
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  3. Shahin Rafii
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Correspondence to Shahin Rafii .

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Editors and Affiliations

  1. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Vinagolu K. Rajasekhar MSc, MPhil, PhD

  2. Invitrogen Corporation, Frederick, MD, USA

    Mohan C. Vemuri Ph.D.

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC, a part of Springer Science+Business Media, LLC

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James, D., Seandel, M., Rafii, S. (2009). Endothelial Ontogeny During Embryogenesis: Role of Cytokine Signaling Pathways. In: Rajasekhar, V.K., Vemuri, M.C. (eds) Regulatory Networks in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60327-227-8_27

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