Development of Blood-Brain Barrier Endothelial Cells

  • Werner Risau
Part of the Advances in Behavioral Biology book series (ABBI, volume 46)


The vascular system of the central nervous system is derived from capillary endothelial cells, which have invaded the early embryonic neuroectoderm. This process is called angiogenesis and is probably regulated by brain-derived factors. Vascular endothelial cell growth factor (VEGF) is an angiogenic growth factor whose expression correlated with embryonic brain angiogenesis, i.e. expression is high in the embryonic brain when angiogenesis occurs and low in the adult brain when angiogenesis is shut off under normal physiological conditions. VEGF receptors 1 and 2 (flt-1 and flk-1) as well as another pair of receptors (tie-1 and tie-2) are receptor tyrosine kinases specifically expressed in endothelial cells. Expression of these receptors is high during brain angiogenesis but low in adult blood-brain barrier endothelium. Signal transduction by these or other receptors involved in endothelial cell growth and differentiatian may be mediated by lyn, a nonreceptor tyrosine kinase expressed in brain endothelium. Induction and maintenance of blood-brain barrier endothelial cell characteristics (complex tight junctions, low number of vesicles, specialized transport systems) are regulated by the local brain environment; e.g. astrocytes. Tight junctions between brain endothelial cells are the structural basis for the paracellular impermeability and high electrical resistance of blood-brain barrier endothelium. Association of tight junction particles with the P-face along with the intercellular adhesion forces rather than the number or branching frequency of tight junction strands correlated with BBB development and function suggesting that the cytoplasmic anchoring of the tight junctions plays an important role.


Tight Junction Brain Endothelial Cell Vascular Endothelial Cell Growth Factor Brain Endothelium Vascular Sprout 
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.


Le réseau vasculaire du système nerveux central dérive des cellules endothéliales capillaires, qui ont envahi le neuroectoderme embryonaire précoce. Le processus appelé angiogénèse est probablement régulé par des facteurs provenant du cerveau. Le facteur de croissance des cellules endothéliales vasculaires (VEGF) est un facteur angiogénique dont l’expression est corrélée à l’angiogénèse du cerveau embryonaire, c’est-à-dire que son expression est élevée dans le cerveau embryonaire quand se produit l’angiogénèse, et faible dans le cerveau adulte, où l’angiogénèse est stoppée dans les les conditions physiologiques normales. Les récepteurs 1 et 2 (flt-1 et flk-1) du VEGF, ainsi qu’une autre paire de récepteurs (tie-1 et tie-2) sont des récepteurs de tyrosine kinase spécifiquement exprimés dans les cellules endothéliales. L’expression de ces récepteurs est importante pendant l’angiogénèse du cerveau, mais est basse au niveau de l’endothélium de la BHE chez l’adulte. La transduction du signal par ces récepteurs, ou par d’autres récepteurs impliqués dans la croissance et la différenciation des cellules endothéliales, peut être médiée par lyn, une tyrosine kinase non récepteur exprimée dans l’endothélium cérébral.L’ induction et le maintien des caractéristiques des cellules endothéliales de la BHE (jonctions occlusives complexes, petit nombre de vésicules, systèmes de transport spécifiques) sont régulés par l’environnement local du cerveau, par exemple les astrocytes.Les jonctions occlusives entre les cellules endothéliales cérébrales sont la structure de base pour l’imperméabilité paracellulaire et la forte résistivité électrique de l’endothélium de la BHE.

L’association des particules de jonction au niveau de la face Pabluminale faisant intervenir des forces d’adhésion intercellulaires plutôt qu’une haute fréquence de branchements ou un nombre élevé de zones de jonctions serr ées est corrélée au développement et à la fonction de la BHE, ce qui suggère que l’ancrage cytoplasmique des jonctions serrées joue un role important.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. I. Achen, M. G., M. Clauss, H. Schnürch, and W. Risau. 1995. The non-receptor tyrosine kinase Lyn is localized in the developing blood-brain barrier. Differentiation. 59: 15–24.Google Scholar
  2. 2.
    Bär, T. 1980. The vascular system of the cerebral cortex. AdvAnat.Embryol.Cell Biol. 59: 1–62.CrossRefGoogle Scholar
  3. 3.
    Breier, G., U. Albrecht, S. Sterrer, and W. Risau. 1992. Expression of vascular endothelial growth-factor during embryonic angiogenesis and endothelial-cell differentiation. Development. 114: 521–532.PubMedGoogle Scholar
  4. 4.
    Breier, G., M. Clauss, and W. Risau. 1995. Coordinate expression of VEGF-receptor 1 (flt-1) and its ligand suggests a paracrine regulation of murine vascular development. Devel. Dynamics. in press.Google Scholar
  5. 5.
    Cereijido, M., L. Gonzâlez-Mariscal, and B. Contreras. 1989. Tight junction: barrier between higher organisms and environment. NIPS. 4: 72–75.Google Scholar
  6. 6.
    Citi, S. 1993. The molecular-organization of tight junctions. J.Cell Biol. 121: 485–489.PubMedCrossRefGoogle Scholar
  7. 7.
    Crone, C., and S.-P. Olesen. 1982. Electrical resistance of brain microvascular endothelium. Brain Res. 241: 49–55.PubMedCrossRefGoogle Scholar
  8. 8.
    Eichmann, A., C. Marcelle, C. Breant, and N. M. LeDouarin. 1993. Two molecules related to the VEGF receptor are expressed in early endothelial-cells during avian embryonic development. Mechanisms of Develop. 42: 33–48.CrossRefGoogle Scholar
  9. 9.
    Engelhardt, B., and W. Risau. 1995. Development of the blood-brain barrier. In New Concepts of a blood-brain barrier. J. Greenwood, D. Begley, M. Segal, and S. Lightman, editors. Plenum, London. in press.Google Scholar
  10. 10.
    Engerman, R. L., D. Pfaffenbach, and M. D. Davis. 1967. Cell turnover of capillaries. Lab.lnvest. 17: 738–743.Google Scholar
  11. 11.
    Ferrara, N., K. Houck, L. Jakeman, and D. W. Leung. 1992. Molecular and biological properties of the vascular endothelial growth-factor family of proteins. Endocrine Reviews. 13: 18–32.PubMedGoogle Scholar
  12. 12.
    Flamme, I., G. Breier, and W. Risau. 1995. Vascular endothelial growth factor (VEGF) and VEGF-receptor 2 (flk-1) are expressed during vasculogenesis and vascular differentiation in the quail embryo. Devel. Biol. 169: 699–712.CrossRefGoogle Scholar
  13. 13.
    Fleming, T. P., M. Hay, Q. Javed, and S. Citi. 1993. Localization of tight junction protein cingulin is temporally and spatially regulated during early mouse development. Development 117: 1135–1144.PubMedGoogle Scholar
  14. 14.
    Fong, G.-H., J. Rossant, M. Gertsenstein, and M. L. Breitman. 1995. Role of the fit-I receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376: 66–70.PubMedCrossRefGoogle Scholar
  15. 15.
    Furuse, M., T. Hirase, M. Itoh, A. Nagafuchi, S. Yonemura, and S. Tsukita. 1993. Occludin–a novel integral membrane-protein localizing at tight junctions. J.Cell Biol. 123: 1777–1788.PubMedCrossRefGoogle Scholar
  16. 16.
    Gumbiner, B., T. Lowenkopf, and D. Apatira. 1991. Identification of a 160-kda polypeptide that binds to the tight junction protein ZO-1. Proc.NatI.Acad.Sc. 88: 3460–3464.CrossRefGoogle Scholar
  17. 17.
    Itoh, M., A. Nagafuchi, S. Yonemura, T. Kitaniyasuda, and S. Tsukita. 1993. The 220-kd protein colocalizing with cadherins in nonepithelial cells is identical to ZO-1, a tight junction associated protein in epithelial-cells - cdna cloning and immunoelectron microscopy. J.Cell Biol. 121:491–502.Google Scholar
  18. 18.
    Millauer, B., L. K. Shawver, K. H. Plate, W. Risau, and A. Ullrich. 1994. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature. 367: 576–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Millauer, B., S. Wizigmann-Voos, H. Schnürch, R. Martinez, N. P. H. Moller, W. Risau, and A. Ullrich. 1993. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72: 835–846.PubMedCrossRefGoogle Scholar
  20. 20.
    Mühleisen, H., H. Wolburg, and E. Betz. 1989. Freeze-fracture analysis of endothelial cell membranes in rabbit carotid arteries subjected to short-term atherogenic stimuli. Virch.Arch.B Cell Pathol. 56: 413–417.CrossRefGoogle Scholar
  21. 21.
    Mustonen, T., and K. Alitalo. 1995. Endothelial receptor tyrosine kinases involved in angiogenesis. J. Cell Biol. 129: 895–898.PubMedCrossRefGoogle Scholar
  22. 22.
    Nagy, Z., H. Peters, and I. Hüttner. 1984. Fracture faces of cell junctions in cerebral endothelium during normal and hyperosmotic conditions. Lab.Invest. 50: 313–322.PubMedGoogle Scholar
  23. 23.
    Nico, B., D. Cantino, M. Bertossi, D. Ribatti, M. Sassoe. and L. Roncali. 1992. Tight endothelial junctions in the developing microvasculature–a thin-section and freeze-fracture study in the chick-embryo optic tectum. J.SubmicrCvtol.P. 24: 85–95.Google Scholar
  24. 24.
    Noden, D. M. 1991. Development of craniofacial blood vessels. In The development of the vascular system. R. N. Feinberg, G. K. Sherer, and R. Auerbach, editors. Karger, Basel. 1–24.Google Scholar
  25. 25.
    Plate, K. H., G. Breier, H. A. Weich, and W. Risau. 1992. Vascular endothelial growth-factor is a potential tumor angiogenesis factor in human gliomas invivo. Nature 359: 845–848.PubMedCrossRefGoogle Scholar
  26. 26.
    Risau, W., and I. Flamme. 1995. Vasculogenesis. Ann. Rev. Cell Devel. Biol. in press.Google Scholar
  27. 27.
    Risau, W., R. Hallmann, and U. Albrecht. 1986. Differentiation-Dependent Expression of Protein in Brain Endothelium during Development of the Blood-Brain Barrier. Dev.Biol. 117:537–545.Google Scholar
  28. 28.
    Risau, W., and V. Lemmon. 1988. Changes in the vascular extracellular matrix during embryonic vasculogenesis and angiogenesis. Dev.Biol. 125: 441–450.PubMedCrossRefGoogle Scholar
  29. 29.
    Risau, W., and H. Wolburg. 1991. The importance of the blood-brain-barrier in fetuses and embryos - reply. TINS. 14: 15.Google Scholar
  30. 30.
    Robertson, P. L., M. Du Bois, P. D. Bowman, and G. W. Goldstein. 1985. Angiogenesis in developing rat brain: an in vivo and in vitro study. Dev.Brain Res. 23: 219–223.CrossRefGoogle Scholar
  31. 31.
    Sato, T. N., Y. Tozawa, U. Deutsch, K. Wolburg-Buchholz, Y. Fujiwara, M. Gendron-Maguire, T. Gridley, H. Wolburg, W. Risau, and Y. Qin. 1995. Distinct roles of the receptor tyrosine kinases tie-1 and tie-2 in blood vessel formation. Nature 376: 70–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Saunders, N. R., K. M. Dziegielewska, and K. Mollgard. 1991. The importance of the blood-brain barrier in fetuses and embryos, letter to the editor. TINS 14: 14.PubMedGoogle Scholar
  33. 33.
    Schnürch, H., and W. Risau. 1993. Expression of tie-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 119: 957–968.PubMedGoogle Scholar
  34. 34.
    Shalaby, F., J. Rossant, T. Yamaguchi, M. Gertsenstein, X.-F. Wu, M. L. Breitman, and A. C. Schuh. 1995. Failure of blood-island formation and vasculogenesis in flk-l-deficient mice. Nature 376: 62–66.PubMedCrossRefGoogle Scholar
  35. 35.
    Simionescu, M., N. Ghinea, A. Fixman, M. Lasser, L. Kukes, N. Simionescu, and G. E. Palade. 1988. The cerebral microvasculature of the rat: structure and luminal surface properties during early development. J.Submicrosc.Cytol. 20: 243–261.Google Scholar
  36. 36.
    Stewart, P. A., and E. M. Hayakawa. 1987. Interendothelialjunctional changes underlie the developmental “tightening” of the blood-brain barrier. Dev.Brain Res. 32: 271–281.CrossRefGoogle Scholar
  37. 37.
    Wakai, S., and N. Hirokawa. 1978. Development of the blood-brain barrier to horseradish peroxidase in the chick embryo. Cell Tissue Res. 195: 195–203.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolbure. I., J. Neuhaus. U. Kniesel, B. Krauss, E. M. Schmid, M. Ocalan, C. Farrell, and W. Risau. 1994. Modulation of tight junction structure in blood-brain-barrier endothelial-cells–effects of tissue-culture, 2nd messengers and cocultured astrocytes.. 1. Cell Sci. 107: 1347–1357.Google Scholar
  39. 39.
    Yamaguchi, T. P., D. J. Dumont, R. A. Conlon, M. L. Breitman, and J. Rossant. 1993. Flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial-cell precursors. Development. 118: 489–498.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Werner Risau
    • 1
  1. 1.Max-Planck-Institut für Physiologische und Klinische Forschung, Abteilung Molekulare ZellbiologieW. G. Kerckhoff-InstitutBad NauheimGermany

Personalised recommendations