How do endothelial cells orientate?

  • Holger Gerhardt
  • Christer Betsholtz
Part of the Experientia Supplementum book series (EXS)


Vascular Endothelial Growth Factor Growth Cone Connective Tissue Growth Factor Stalk Cell VEGFR2 Activation 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Claxton S, Fruttiger M (2003) Role of arteries in oxygen induced vaso-obliteration. Exp Eye Res 77: 305–311PubMedCrossRefGoogle Scholar
  2. 2.
    Benjamin LE, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125: 1591–1598PubMedGoogle Scholar
  3. 3.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386: 671–674PubMedCrossRefGoogle Scholar
  4. 4.
    Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D et al. (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol161: 1163–1177PubMedCrossRefGoogle Scholar
  5. 5.
    Serini G, Ambrosi D, Giraudo E, Gamba A, Preziosi L, Bussolino F (2003) Modeling the early stages of vascular network assembly. EMBO J 22: 1771–1779PubMedCrossRefGoogle Scholar
  6. 6.
    Samakovlis C, Hacohen N, Manning G, Sutherland DC, Guillemin K, Krasnow MA (1996) Development of the Drosophila tracheal system occurs by a series of morphologically distinct but genetically coupled branching events. Development 122: 1395–1407PubMedGoogle Scholar
  7. 7.
    Lee SH, Schloss DJ, Jarvis L, Krasnow MA, Swain JL (2001) Inhibition of angiogenesis by a mouse sprouty protein. J Biol Chem 276: 4128–4133PubMedCrossRefGoogle Scholar
  8. 8.
    Adryan B, Decker HJ, Papas TS, Hsu T (2000) Tracheal development and the von Hippel-Lindau tumor suppressor homolog in Drosophila. Oncogene 19: 2803–2811PubMedCrossRefGoogle Scholar
  9. 9.
    Sutherland D, Samakovlis C, Krasnow MA (1996) Branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87: 1091–1101PubMedCrossRefGoogle Scholar
  10. 10.
    Jarecki J, Johnson E, Krasnow MA (1999) Oxygen regulation of airway branching in Drosophila is mediated by branchless FGF. Cell 99: 211–220PubMedCrossRefGoogle Scholar
  11. 11.
    Ribeiro C, Ebner A, Affolter M (2002) In vivo imaging reveals different cellular functions for FGF and Dpp signaling in tracheal branching morphogenesis. Dev Cell 2: 677–683PubMedCrossRefGoogle Scholar
  12. 12.
    Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA (1998) Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92: 253–263PubMedCrossRefGoogle Scholar
  13. 13.
    Wolf C, Gerlach N, Schuh R (2002) Drosophilatracheal system formation involves FGF-dependent cell extensions contacting bridge-cells. EMBO Rep 3: 563–568PubMedCrossRefGoogle Scholar
  14. 14.
    Steneberg P, Hemphala J, Samakovlis C (1999) Dpp and Notch specify the fusion cell fate in the dorsal branches of the Drosophila trachea. Mech Dev 87: 153–163PubMedCrossRefGoogle Scholar
  15. 15.
    Marin-Padilla M (1985) Early vascularization of the embryonic cerebral cortex: Golgi and electron microscopic studies. J Comp Neurol 241: 237–249PubMedCrossRefGoogle Scholar
  16. 16.
    Ausprunk DH, Folkman J (1977) Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res 14: 53–65PubMedCrossRefGoogle Scholar
  17. 17.
    Sholley MM, Ferguson GP, Seibel HR, Montour JL, Wilson JD (1984) Mechanisms of neovascularization. Vascular sprouting can occur without proliferation of endothelial cells. Lab Invest 51: 624–634PubMedGoogle Scholar
  18. 18.
    Clark ER, Clark EL (1939) Microscopic observations on the growth of blood capillaries in the living mammal. Am J Anat 64: 251–301CrossRefGoogle Scholar
  19. 19.
    Kurz H, Gartner T, Eggli PS, Christ B (1996) First blood vessels in the avian neural tube are formed by a combination of dorsal angioblast immigration and ventral sprouting of endothelial cells. Dev Biol 173: 133–147PubMedCrossRefGoogle Scholar
  20. 20.
    Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C, Shima DT (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Gene Dev 16: 2684–2698PubMedCrossRefGoogle Scholar
  21. 21.
    Dorrell MI, Aguilar E, Friedlander M (2002) Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest Ophthalmol Visual Sci 43: 3500–3510Google Scholar
  22. 22.
    Gritli-Linde A, Lewis P, McMahon AP, Linde A (2001) The whereabouts of a morphogen: direct evidence for short-and graded long-range activity of hedgehog signaling peptides. Dev Biol 236: 364–386PubMedCrossRefGoogle Scholar
  23. 23.
    McFarlane S (2000) Attraction versus repulsion: The growth cone decides. Biochem Cell Biol 78: 563–568PubMedCrossRefGoogle Scholar
  24. 24.
    Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266: 11947–11954PubMedGoogle Scholar
  25. 25.
    Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267: 26031–26037PubMedGoogle Scholar
  26. 26.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9: 669–676PubMedCrossRefGoogle Scholar
  27. 27.
    Haigh JJ, Gerhardt H, Morelli P, Haigh K, Tsien J, Damert A, Miquerol L, Muhlner U, Klein R, Ferrara N et al. (2003) Cortical and retinal defects caused by dosage dependent reductions in VEGF-A paracrine signaling. Dev Biol 262: 225–241PubMedCrossRefGoogle Scholar
  28. 28.
    Sato M, Kornberg TB (2002) FGF is an essential mitogen and chemoattractant for the air sacs of the Drosophila tracheal system. Dev Cell 3: 195–207PubMedCrossRefGoogle Scholar
  29. 29.
    Baier H, Bonhoeffer F (1992) Axon guidance by gradients of a target-derived component. Science 255: 472–475PubMedADSCrossRefGoogle Scholar
  30. 30.
    Baier H, Bonhoeffer F (1994) Attractive axon guidance molecules. Science 265: 1541–1542PubMedADSCrossRefGoogle Scholar
  31. 31.
    Tessier-Lavigne M, Goodman CS (1996) The molecular biology of axon guidance. Science 274: 1123–1133PubMedCrossRefADSGoogle Scholar
  32. 32.
    Goodman CS (1996) Mechanisms and molecules that control growth cone guidance. Annu Rev Neurosci 19: 341–377PubMedCrossRefGoogle Scholar
  33. 33.
    Koleske AJ (2003) Do filopodia enable the growth cone to find its way? Sci STKE 183: pe 20Google Scholar
  34. 34.
    Davenport RW, Dou P, Rehder V, Kater SB (1993) A sensory role for neuronal growth cone filopodia. Nature 361: 721–724PubMedCrossRefADSGoogle Scholar
  35. 35.
    Zheng JQ, Wan JJ, Poo MM (1996) Essential role of filopodia in chemotropic turning of nerve growth cone induced by a glutamate gradient. J Neurosci 16: 1140–1149PubMedGoogle Scholar
  36. 36.
    Goodhill GJ, Urbach JS (1999) Theoretical analysis of gradient detection by growth cones. J Neurobiol 41: 230–241PubMedCrossRefGoogle Scholar
  37. 37.
    Aletta JM, Greene LA (1988) Growth cone configuration and advance: a time-lapse study using video-enhanced differential interference contrast microscopy. J Neurosci 8: 1425–1435PubMedGoogle Scholar
  38. 38.
    Wu DY, Wang LC, Mason CA, Goldberg DJ (1996) Association of beta 1 integrin with phosphotyrosine in growth cone filopodia. J Neurosci 16: 1470–1478PubMedGoogle Scholar
  39. 39.
    Cheng S, Mao J, Rehder V (2000) Filopodial behavior is dependent on the phosphorylation state of neuronal growth cones. Cell Motil Cytoskeleton 47: 337–350PubMedCrossRefGoogle Scholar
  40. 40.
    Grabham PW, Goldberg DJ (1997) Nerve growth factor stimulates the accumulation of beta1 integrin at the tips of filopodia in the growth cones of sympathetic neurons. J Neurosci 17: 5455–5465PubMedGoogle Scholar
  41. 41.
    Grabham PW, Foley M, Umeojiako A, Goldberg DJ (2000) Nerve growth factor stimulates coupling of beta1 integrin to distinct transport mechanisms in the filopodia of growth cones. J Cell Sci 113 (Pt 17): 3003–3012PubMedGoogle Scholar
  42. 42.
    Bagri A, Tessier-Lavigne M (2002) Neuropilins as Semaphorin receptors: in vivo functions in neuronal cell migration and axon guidance. Adv Exp Med Biol 515: 13–31PubMedGoogle Scholar
  43. 43.
    Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92: 735–745PubMedCrossRefGoogle Scholar
  44. 44.
    Soker S (2001) Neuropilin in the midst of cell migration and retraction. Int J Biochem Cell Biol 33: 433–437PubMedCrossRefGoogle Scholar
  45. 45.
    Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H (1999) A requirement for neuropilin-1 in embryonic vessel formation. Development 126: 4895–4902PubMedGoogle Scholar
  46. 46.
    Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, Niwa H, Miyazaki J, Hirota S, Kitamura Y et al. (2002) Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA 99: 3657–3662PubMedCrossRefADSGoogle Scholar
  47. 47.
    Gu C, Rodriguez ER, Reimert DV, Shu T, Fritzsch B, Richards LJ, Kolodkin AL, Ginty DD (2003) Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev Cell 5: 45–57PubMedzbMATHCrossRefGoogle Scholar
  48. 48.
    Adams RH (2002) Vascular patterning by Eph receptor tyrosine kinases and ephrins. Semin Cell Dev Biol 13: 55–60PubMedCrossRefGoogle Scholar
  49. 49.
    Adams RH, Klein R (2000) Eph receptors and ephrin ligands. essential mediators of vascular development. Trends Cardiovasc Med 10: 183–188PubMedCrossRefGoogle Scholar
  50. 50.
    Liu ZJ, Herlin M (2003) Slit-Robo: Neuronal guides signal in tumor angiogenesis. Cancer Cell 4: 1–2PubMedCrossRefGoogle Scholar
  51. 51.
    Stalmans I, Yin-Shan N, Rohan R, Fruttiger M, Bouché A, Ÿuce A, Fijusawa H, Hermans B, Shan M, Jansen S et al. (2002) Arteriolar and venolar patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109: 327–336PubMedCrossRefGoogle Scholar
  52. 52.
    Mattot V, Moons L, Lupu F, Chernavvsky D, Gomez RA, Collen D, Carmeliet P (2002) Loss of the VEGF(164) and VEGF(188) isoforms impairs postnatal glomerular angiogenesis and renal arteriogenesis in mice. J Am Soc Nephrol 13: 1548–1560PubMedCrossRefGoogle Scholar
  53. 53.
    Yu JL, Rak JW, Klement G, Kerbel RS (2002) Vascular endothelial growth factor isoform expression as a determinant of blood vessel patterning in human melanoma xenografts. Cancer Res 62: 1838–1846PubMedGoogle Scholar
  54. 54.
    Ishida S, Usui T, Yamashiro K, Kaji Y, Amano S, Ogura Y, Hida T, Oguchi Y, Ambati J, Miller J et al. (2003) VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 198: 483–489PubMedCrossRefGoogle Scholar
  55. 55.
    Shima DT, Gougos A, Miller JW, Tolentino M, Robinson G, Adamis AP, D’Amore PA (1996) Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of Macaca fascicularis. Invest Ophthalmol Visual Sci 37: 1334–1340Google Scholar
  56. 56.
    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z et al. (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2: 737–744PubMedCrossRefGoogle Scholar
  57. 57.
    Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y (2002) Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J Biol Chem 277: 36288–36295PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2005

Authors and Affiliations

  • Holger Gerhardt
    • 1
  • Christer Betsholtz
    • 2
  1. 1.Vascular Biology LaboratoryCancer Research UKLondonUK
  2. 2.Laboratory of Vascular Biology Division of Matrix Biology, House A3, Plan 4, Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden

Personalised recommendations