Angiogenesis

, Volume 12, Issue 2, pp 165–175

Fibronectins in vascular morphogenesis

Review Paper

Abstract

Fibronectin is an extracellular matrix protein found only in vertebrate organisms containing endothelium-lined vasculature and is required for cardiovascular development in fish and mice. Fibronectin and its splice variants containing EIIIA and EIIIB domains are highly upregulated around newly developing vasculature during embryogenesis and in pathological conditions including atherosclerosis, cardiac hypertrophy, and tumorigenesis. However, their molecular roles in these processes are not entirely understood. We review genetic studies examining functions of fibronectin and its splice variants during embryonic cardiovascular development, and discuss potential roles of fibronectin in vascular disease and tumor angiogenesis.

Keywords

Alternative splicing Angiogenesis Cardiovascular development Endothelium Integrins Pericyte Vascular smooth muscle 

References

  1. 1.
    Coultas L et al (2005) Endothelial cells and VEGF in vascular development. Nature 438:937–945PubMedGoogle Scholar
  2. 2.
    Hodivala-Dilke K (2008) Alphavbeta3 integrin and angiogenesis: a moody integrin in a changing environment. Curr Opin Cell Biol 20:514–519PubMedGoogle Scholar
  3. 3.
    Hynes RO (2007) Cell-matrix adhesion in vascular development. J Thromb Haemost 5(Suppl 1):32–40PubMedGoogle Scholar
  4. 4.
    Armulik A et al (2005) Endothelial/pericyte interactions. Circ Res 97:512–523PubMedGoogle Scholar
  5. 5.
    Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7:452–464PubMedGoogle Scholar
  6. 6.
    von Tell D et al (2006) Pericytes and vascular stability. Exp Cell Res 312:623–629Google Scholar
  7. 7.
    George EL et al (1997) Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells. Blood 90:3073–3081PubMedGoogle Scholar
  8. 8.
    George EL et al (1993) Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119:1079–1091PubMedGoogle Scholar
  9. 9.
    Georges-Labouesse EN et al (1996) Mesodermal development in mouse embryos mutant for fibronectin. Dev Dyn 207:145–156PubMedGoogle Scholar
  10. 10.
    Francis SE et al (2002) Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 22:927–933PubMedGoogle Scholar
  11. 11.
    Lucitti JL et al (2007) Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development 134:3317–3326PubMedGoogle Scholar
  12. 12.
    Astrof S et al (2007) Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four. Mech Dev 124:551–558PubMedGoogle Scholar
  13. 13.
    Trinh LA, Stainier DY (2004) Fibronectin regulates epithelial organization during myocardial migration in zebrafish. Dev Cell 6:371–382PubMedGoogle Scholar
  14. 14.
    Koshida S et al (2005) Integrinalpha5-dependent fibronectin accumulation for maintenance of somite boundaries in zebrafish embryos. Dev Cell 8:587–598PubMedGoogle Scholar
  15. 15.
    Marsden M, DeSimone DW (2001) Regulation of cell polarity, radial intercalation and epiboly in Xenopus: novel roles for integrin and fibronectin. Development 128:3635–3647PubMedGoogle Scholar
  16. 16.
    Katsuno T et al (2008) Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol Biol Cell 19:2465–2475PubMedGoogle Scholar
  17. 17.
    Ikenouchi J et al (2007) Requirement of ZO-1 for the formation of belt-like adherens junctions during epithelial cell polarization. J Cell Biol 176:779–786PubMedGoogle Scholar
  18. 18.
    Umeda K et al (2006) ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell 126:741–754PubMedGoogle Scholar
  19. 19.
    Buchner DA et al (2007) Pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proc Natl Acad Sci U S A 104:13996–14001PubMedGoogle Scholar
  20. 20.
    Kamei M et al (2006) Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442:453–456PubMedGoogle Scholar
  21. 21.
    Koh W et al (2008) Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling. J Cell Sci 121:989–1001PubMedGoogle Scholar
  22. 22.
    Giancotti FG, Tarone G (2003) Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu Rev Cell Dev Biol 19:173–206PubMedGoogle Scholar
  23. 23.
    Hynes RO et al (2002) The diverse roles of integrins and their ligands in angiogenesis. Cold Spring Harb Symp Quant Biol 67:143–153PubMedGoogle Scholar
  24. 24.
    Yang JT, Hynes RO (1996) Fibronectin receptor functions in embryonic cells deficient in alpha 5 beta 1 integrin can be replaced by alpha V integrins. Mol Biol Cell 7:1737–1748PubMedGoogle Scholar
  25. 25.
    Taverna D, Hynes RO (2001) Reduced blood vessel formation and tumor growth in alpha5-integrin-negative teratocarcinomas and embryoid bodies. Cancer Res 61:5255–5261PubMedGoogle Scholar
  26. 26.
    Aota S et al (1994) The short amino acid sequence Pro-His-Ser-Arg-Asn in human fibronectin enhances cell-adhesive function. J Biol Chem 269:24756–24761PubMedGoogle Scholar
  27. 27.
    Hynes RO (1990) Fibronectins. Springer-Verlag, New YorkGoogle Scholar
  28. 28.
    Takahashi S et al (2007) The RGD motif in fibronectin is essential for development but dispensable for fibril assembly. J Cell Biol 178:167–178PubMedGoogle Scholar
  29. 29.
    Bader BL et al (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95:507–519PubMedGoogle Scholar
  30. 30.
    Grazioli A et al (2006) Defective blood vessel development and pericyte/pvSMC distribution in alpha 4 integrin-deficient mouse embryos. Dev Biol 293:165–177PubMedGoogle Scholar
  31. 31.
    Wijelath ES et al (2002) Novel vascular endothelial growth factor binding domains of fibronectin enhance vascular endothelial growth factor biological activity. Circ Res 91:25–31PubMedGoogle Scholar
  32. 32.
    Wijelath ES et al (2006) Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: enhancement of VEGF biological activity by a singular growth factor/matrix protein synergism. Circ Res 99:853–860PubMedGoogle Scholar
  33. 33.
    Lee S et al (2005) Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169:681–691PubMedGoogle Scholar
  34. 34.
    Carmeliet P et al (1999) Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 5:495–502PubMedGoogle Scholar
  35. 35.
    Maes C et al (2004) Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J Clin Invest 113:188–199PubMedGoogle Scholar
  36. 36.
    Zhou X et al (2008) Fibronectin fibrillogenesis regulates three-dimensional neovessel formation. Genes Dev 22:1231–1243PubMedGoogle Scholar
  37. 37.
    Bayless et al (2000) RGD-dependent vacuolation and lumen formation observed during endothelial cell morphogenesis in three-dimensional fibrin matrices involves the alpha(v)beta(3) and alpha(5)beta(1) integrins. Am J Pathol 156:1673–1683PubMedGoogle Scholar
  38. 38.
    McCarty JH et al (2002) Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol Cell Biol 22:7667–7677PubMedGoogle Scholar
  39. 39.
    Yang JT et al (1999) Overlapping and independent functions of fibronectin receptor integrins in early mesodermal development. Dev Biol 215:264–277PubMedGoogle Scholar
  40. 40.
    Carlson TR et al (2008) Cell-autonomous requirement for beta1 integrin in endothelial cell adhesion migration and survival during angiogenesis in mice. Development 135:2193–2202PubMedGoogle Scholar
  41. 41.
    Wierzbicka-Patynowski I, Schwarzbauer JE (2003) The ins and outs of fibronectin matrix assembly. J Cell Sci 116:3269–3276PubMedGoogle Scholar
  42. 42.
    White ES et al (2008) New insights into form and function of fibronectin splice variants. J Pathol 216:1–14PubMedGoogle Scholar
  43. 43.
    Astrof S et al (2007) Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin. Dev Biol 311:11–24PubMedGoogle Scholar
  44. 44.
    Dickson MC et al (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121:1845–1854PubMedGoogle Scholar
  45. 45.
    Ferrara N et al (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442PubMedGoogle Scholar
  46. 46.
    Lee SH et al (2000) Maintenance of vascular integrity in the embryo requires signaling through the fibroblast growth factor receptor. J Biol Chem 275:33679–33687PubMedGoogle Scholar
  47. 47.
    Suri C et al (1996) Requisite role of angiopoietin–1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180PubMedGoogle Scholar
  48. 48.
    Miyamoto S et al (1996) Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol 135:1633–1642PubMedGoogle Scholar
  49. 49.
    Reinhart-King CA et al (2005) The dynamics and mechanics of endothelial cell spreading. Biophys J 89:676–689PubMedGoogle Scholar
  50. 50.
    Davidson LA et al (2008) Live imaging of cell protrusive activity, and extracellular matrix assembly and remodeling during morphogenesis in the frog, Xenopus laevis. Dev Dyn 237:2684–2692PubMedGoogle Scholar
  51. 51.
    Erickson HP (1994) Reversible unfolding of fibronectin type III and immunoglobulin domains provides the structural basis for stretch and elasticity of titin and fibronectin. Proc Natl Acad Sci U S A 91:10114–10118PubMedGoogle Scholar
  52. 52.
    Liao YF et al (2002) The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J Biol Chem 277:14467–14474PubMedGoogle Scholar
  53. 53.
    Okamura Y et al (2001) The extra domain A of fibronectin activates toll-like receptor 4. J Biol Chem 276:10229–10233PubMedGoogle Scholar
  54. 54.
    Shinde AV et al (2008) Identification of the peptide sequences within the EIIIA (EDA) segment of fibronectin that mediate integrin alpha9beta1-dependent cellular activities. J Biol Chem 283:2858–2870PubMedGoogle Scholar
  55. 55.
    Huang XZ et al (2000) Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Mol Cell Biol 20:5208–5215PubMedGoogle Scholar
  56. 56.
    Li S et al (2003) The serum response factor coactivator myocardin is required for vascular smooth muscle development. Proc Natl Acad Sci U S A 100:9366–9370PubMedGoogle Scholar
  57. 57.
    Serini G et al (1998) The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol 142:873–881PubMedGoogle Scholar
  58. 58.
    High FA et al (2007) An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J Clin Invest 117:353–363PubMedGoogle Scholar
  59. 59.
    Hirschi et al (2003) Gap junction communication mediates transforming growth factor-{beta} activation and endothelial-induced mural cell differentiation. Circ Res 93:429–437PubMedGoogle Scholar
  60. 60.
    Wurdak H et al (2005) Inactivation of TGF{beta} signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome. Genes Dev 19:530–535PubMedGoogle Scholar
  61. 61.
    Lindblom P et al (2003) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17:1835–1840PubMedGoogle Scholar
  62. 62.
    Abramsson A et al (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest 112:1142–1151PubMedGoogle Scholar
  63. 63.
    Hellstrom M et al (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055PubMedGoogle Scholar
  64. 64.
    Majesky MW (2007) Developmental basis of vascular smooth muscle diversity. Arterioscler Thromb Vasc Biol 27:1248–1258PubMedGoogle Scholar
  65. 65.
    Esner M et al (2006) Smooth muscle of the dorsal aorta shares a common clonal origin with skeletal muscle of the myotome. Development 133:737–749PubMedGoogle Scholar
  66. 66.
    Snider P et al (2007) Cardiovascular development and the colonizing cardiac neural crest lineage. Scientific World J 7:1090–1113Google Scholar
  67. 67.
    Ffrench-Constant C, Hynes RO (1988) Patterns of fibronectin gene expression and splicing during cell migration in chicken embryos. Development 104:369–382PubMedGoogle Scholar
  68. 68.
    Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660PubMedGoogle Scholar
  69. 69.
    Cascone I et al (2005) Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang–1. J Cell Biol 170:993–1004PubMedGoogle Scholar
  70. 70.
    Sheppard J et al (1994) Expanding roles for alpha 4 integrin and its ligands in development. Cell Adhes Commun 2:27–43PubMedGoogle Scholar
  71. 71.
    Vlahakis NE et al (2005) The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. J Biol Chem 280:4544–4552PubMedGoogle Scholar
  72. 72.
    Bergers G et al (1999) Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 284:808–812PubMedGoogle Scholar
  73. 73.
    Bergers G et al (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295PubMedGoogle Scholar
  74. 74.
    Morikawa S et al (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000PubMedGoogle Scholar
  75. 75.
    Benjamin LE, Keshet E (1997) Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci USA 94:8761–8766PubMedGoogle Scholar
  76. 76.
    Sennino B et al (2007) Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res 67:7358–7367PubMedGoogle Scholar
  77. 77.
    Owens GK et al (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84:767–801PubMedGoogle Scholar
  78. 78.
    Dzau VJ et al (2002) Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med 8:1249–1256PubMedGoogle Scholar
  79. 79.
    Glukhova MA et al (1989) Expression of extra domain A fibronectin sequence in vascular smooth muscle cells is phenotype dependent. J Cell Biol 109:357–366PubMedGoogle Scholar
  80. 80.
    Rosamond W et al (2007) Heart disease and stroke statistics-2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115:e69–e171PubMedGoogle Scholar
  81. 81.
    Babaev VR et al (2008) Absence of regulated splicing of fibronectin EDA exon reduces atherosclerosis in mice. Atherosclerosis 197:534–540PubMedGoogle Scholar
  82. 82.
    Tan MH et al (2004) Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis. Blood 104:11–18PubMedGoogle Scholar
  83. 83.
    Dangas G, Kuepper F (2002) Cardiology patient page. Restenosis: repeat narrowing of a coronary artery: prevention and treatment. Circulation 105:2586–2587PubMedGoogle Scholar
  84. 84.
    Dubin D et al (1995) Balloon catheterization induces arterial expression of embryonic fibronectins. Arterioscler Thromb Vasc Biol 15:1958–1967PubMedGoogle Scholar
  85. 85.
    Samuel JL et al (1991) Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload. J Clin Invest 88:1737–1746PubMedGoogle Scholar
  86. 86.
    Coito AJ et al (1997) Expression of fibronectin splicing variants in organ transplantation: a differential pattern between rat cardiac allografts and isografts. Am J Pathol 150:1757–1772PubMedGoogle Scholar
  87. 87.
    Cai CL et al (2008) A myocardial lineage derives from Tbx18 epicardial cells. Nature 454:104–108PubMedGoogle Scholar
  88. 88.
    Zhou B et al (2008) Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454:109–113PubMedGoogle Scholar
  89. 89.
    Lepilina A et al (2006) A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127:607–619PubMedGoogle Scholar
  90. 90.
    Castellani P et al (1994) The fibronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis. Int J Cancer 59:612–618PubMedGoogle Scholar
  91. 91.
    Castellani P et al (2002) Differentiation between high- and low-grade astrocytoma using a human recombinant antibody to the extra domain-B of fibronectin. Am J Pathol 161:1695–1700PubMedGoogle Scholar
  92. 92.
    D’Ovidio MC et al (1998) Intratumoral microvessel density and expression of ED-A/ED-B sequences of fibronectin in breast carcinoma. Eur J Cancer 34:1081–1085PubMedGoogle Scholar
  93. 93.
    Inufusa H et al (1995) Localization of oncofetal and normal fibronectin in colorectal cancer. Correlation with histologic grade, liver metastasis, and prognosis. Cancer 75:2802–2808PubMedGoogle Scholar
  94. 94.
    Kaczmarek J et al (1994) Distribution of oncofetal fibronectin isoforms in normal, hyperplastic and neoplastic human breast tissues. Int J Cancer 59:11–16PubMedGoogle Scholar
  95. 95.
    Lohi J et al (1995) Tenascin and fibronectin isoforms in human renal cell carcinomas, renal cell carcinoma cell lines and xenografts in nude mice. Int J Cancer 63:442–449PubMedGoogle Scholar
  96. 96.
    Kosmehl H et al (1999) Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinoma. Br J Cancer 81:1071–1079PubMedGoogle Scholar
  97. 97.
    Matsumoto E et al (1999) Expression of fibronectin isoforms in human breast tissue: production of extra domain A +/extra domain B + by cancer cells and extra domain A + by stromal cell. Jap J Cancer Res 90:320–325Google Scholar
  98. 98.
    Oyama F et al (1989) Deregulation of alternative splicing of fibronectin pre-mRNA in malignant human liver tumors. J Biol Chem 264:10331–10334PubMedGoogle Scholar
  99. 99.
    Oyama F et al (1990) Oncodevelopmental regulation of the alternative splicing of fibronectin pre-messenger RNA in human lung tissues. Cancer Res 50:1075–1078PubMedGoogle Scholar
  100. 100.
    Pujuguet P et al (1996) Expression of fibronectin ED-A + and ED-B + isoforms by human and experimental colorectal cancer. Contribution of cancer cells and tumor-associated myofibroblasts. Am J Pathol 148:579–592PubMedGoogle Scholar
  101. 101.
    Scarpino S et al (1999) Expression of EDA/EDB isoforms of fibronectin in papillary carcinoma of the thyroid. J Pathol 188:163–167PubMedGoogle Scholar
  102. 102.
    Ohnishi T et al (1998) Role of fibronectin-stimulated tumor cell migration in glioma invasion in vivo: clinical significance of fibronectin and fibronectin receptor expressed in human glioma tissues. Clin Exp Metastasis 16:729–741PubMedGoogle Scholar
  103. 103.
    Astrof S et al (2004) Direct test of potential roles of EIIIA and EIIIB alternatively spliced segments of fibronectin in physiological and tumor angiogenesis. Mol Cell Biol 24:8662–8670PubMedGoogle Scholar
  104. 104.
    Ruoslahti E (2002) Specialization of tumour vasculature. Nat Rev Cancer 2:83–90PubMedGoogle Scholar
  105. 105.
    Borsi L et al (2002) Selective targeting of tumoral vasculature: comparison of different formats of an antibody (L19) to the ED-B domain of fibronectin. Int J Cancer 102:75–85PubMedGoogle Scholar
  106. 106.
    Nilsson F et al (2001) Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice. Cancer Res 61:711–716PubMedGoogle Scholar
  107. 107.
    Kaspar M et al (2006) Fibronectin as target for tumor therapy. Int J Cancer 118:1331–1339PubMedGoogle Scholar
  108. 108.
    Villa A et al (2008) A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo. Int J Cancer 122:2405–2413PubMedGoogle Scholar
  109. 109.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62PubMedGoogle Scholar
  110. 110.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedGoogle Scholar
  111. 111.
    Batchelor TT et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Greenberg Division of Cardiology, Department of Medicine, Department of Cell and Developmental BiologyWeill Medical College of Cornell UniversityNew YorkUSA
  2. 2.Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research at MITCambridgeUSA

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