Skip to main content
PMC home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1994 Jul 2;126(2):465–473. doi: 10.1083/jcb.126.2.465

Upregulation of the low density lipoprotein receptor at the blood-brain barrier: intercommunications between brain capillary endothelial cells and astrocytes

PMCID: PMC2200038  PMID: 8034745

Abstract

In contrast to the endothelial cells in large vessels where LDL receptors are downregulated, brain capillary endothelial cells in vivo express an LDL receptor. Using a cell culture model of the blood-brain barrier consisting of a coculture of brain capillary endothelial cells and astrocytes, we observed that the capacity of endothelial cells to bind LDL is enhanced threefold when cocultured with astrocytes. We next investigated the ability of astrocytes to modulate endothelial cell LDL receptor expression. We have shown that the lipid requirement of astrocytes increases the expression of endothelial cell LDL receptors. Experiments with dialysis membranes of different pore size showed that this effect is mediated by a soluble factor(s) with relative molecular mass somewhere between 3,500 and 14,000. Substituting astrocytes with smooth muscle cells or brain endothelium with endothelium from the aorta or the adrenal cortex did not enhance the luminal LDL receptor expression on endothelial cells, demonstrating the specificity of the interactions. This factor(s) is exclusively secreted by astrocytes cocultured with brain capillary endothelial cells, but it also upregulates the LDL receptor on other cell types. This study confirms the notion that the final fine tuning of cell differentiation is under local control.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BORNSTEIN M. B. Reconstituted rattail collagen used as substrate for tissue cultures on coverslips in Maximow slides and roller tubes. Lab Invest. 1958 Mar-Apr;7(2):134–137. [PubMed] [Google Scholar]
  2. Barbaras R., Grimaldi P., Négrel R., Ailhaud G. Binding of lipoproteins and regulation of cholesterol synthesis in cultured mouse adipose cells. Biochim Biophys Acta. 1985 Jun 30;845(3):492–501. doi: 10.1016/0167-4889(85)90215-0. [DOI] [PubMed] [Google Scholar]
  3. Beisiegel U., Schneider W. J., Goldstein J. L., Anderson R. G., Brown M. S. Monoclonal antibodies to the low density lipoprotein receptor as probes for study of receptor-mediated endocytosis and the genetics of familial hypercholesterolemia. J Biol Chem. 1981 Nov 25;256(22):11923–11931. [PubMed] [Google Scholar]
  4. Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
  5. Booher J., Sensenbrenner M. Growth and cultivation of dissociated neurons and glial cells from embryonic chick, rat and human brain in flask cultures. Neurobiology. 1972;2(3):97–105. [PubMed] [Google Scholar]
  6. Brown M. S., Kovanen P. T., Goldstein J. L. Regulation of plasma cholesterol by lipoprotein receptors. Science. 1981 May 8;212(4495):628–635. doi: 10.1126/science.6261329. [DOI] [PubMed] [Google Scholar]
  7. Cancilla P. A., DeBault L. E. Neutral amino acid transport properties of cerebral endothelial cells in vitro. J Neuropathol Exp Neurol. 1983 Mar;42(2):191–199. doi: 10.1097/00005072-198303000-00008. [DOI] [PubMed] [Google Scholar]
  8. Chamoux M., Dehouck M. P., Fruchart J. C., Spik G., Montreuil J., Cecchelli R. Characterization of angiogenin receptors on bovine brain capillary endothelial cells. Biochem Biophys Res Commun. 1991 Apr 30;176(2):833–839. doi: 10.1016/s0006-291x(05)80261-x. [DOI] [PubMed] [Google Scholar]
  9. Dehouck M. P., Jolliet-Riant P., Brée F., Fruchart J. C., Cecchelli R., Tillement J. P. Drug transfer across the blood-brain barrier: correlation between in vitro and in vivo models. J Neurochem. 1992 May;58(5):1790–1797. doi: 10.1111/j.1471-4159.1992.tb10055.x. [DOI] [PubMed] [Google Scholar]
  10. Dehouck M. P., Méresse S., Delorme P., Fruchart J. C., Cecchelli R. An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J Neurochem. 1990 May;54(5):1798–1801. doi: 10.1111/j.1471-4159.1990.tb01236.x. [DOI] [PubMed] [Google Scholar]
  11. Estrada C., Bready J. V., Berliner J. A., Pardridge W. M., Cancilla P. A. Astrocyte growth stimulation by a soluble factor produced by cerebral endothelial cells in vitro. J Neuropathol Exp Neurol. 1990 Nov;49(6):539–549. doi: 10.1097/00005072-199011000-00001. [DOI] [PubMed] [Google Scholar]
  12. Fishman A. P. Endothelium: a distributed organ of diverse capabilities. Ann N Y Acad Sci. 1982;401:1–8. doi: 10.1111/j.1749-6632.1982.tb25702.x. [DOI] [PubMed] [Google Scholar]
  13. Fredrickson D. S., Levy R. I., Lees R. S. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967 Jan 5;276(1):34–contd. doi: 10.1056/NEJM196701052760107. [DOI] [PubMed] [Google Scholar]
  14. Goldstein J. L., Brown M. S. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem. 1977;46:897–930. doi: 10.1146/annurev.bi.46.070177.004341. [DOI] [PubMed] [Google Scholar]
  15. Gospodarowicz D., Massoglia S., Cheng J., Fujii D. K. Effect of fibroblast growth factor and lipoproteins on the proliferation of endothelial cells derived from bovine adrenal cortex, brain cortex, and corpus luteum capillaries. J Cell Physiol. 1986 Apr;127(1):121–136. doi: 10.1002/jcp.1041270116. [DOI] [PubMed] [Google Scholar]
  16. Hofmann S. L., Russell D. W., Goldstein J. L., Brown M. S. mRNA for low density lipoprotein receptor in brain and spinal cord of immature and mature rabbits. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6312–6316. doi: 10.1073/pnas.84.17.6312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Janzer R. C., Raff M. C. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature. 1987 Jan 15;325(6101):253–257. doi: 10.1038/325253a0. [DOI] [PubMed] [Google Scholar]
  18. Joó F. The cerebral microvessels in culture, an update. J Neurochem. 1992 Jan;58(1):1–17. doi: 10.1111/j.1471-4159.1992.tb09272.x. [DOI] [PubMed] [Google Scholar]
  19. Kenagy R., Bierman E. L., Schwartz S., Albers J. J. Metabolism of low density lipoprotein by bovine endothelial cells as a function of cell density. Arteriosclerosis. 1984 Jul-Aug;4(4):365–371. doi: 10.1161/01.atv.4.4.365. [DOI] [PubMed] [Google Scholar]
  20. Méresse S., Dehouck M. P., Delorme P., Bensaïd M., Tauber J. P., Delbart C., Fruchart J. C., Cecchelli R. Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J Neurochem. 1989 Nov;53(5):1363–1371. doi: 10.1111/j.1471-4159.1989.tb08526.x. [DOI] [PubMed] [Google Scholar]
  21. Méresse S., Delbart C., Fruchart J. C., Cecchelli R. Low-density lipoprotein receptor on endothelium of brain capillaries. J Neurochem. 1989 Aug;53(2):340–345. doi: 10.1111/j.1471-4159.1989.tb07340.x. [DOI] [PubMed] [Google Scholar]
  22. Pitas R. E., Boyles J. K., Lee S. H., Foss D., Mahley R. W. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta. 1987 Jan 13;917(1):148–161. doi: 10.1016/0005-2760(87)90295-5. [DOI] [PubMed] [Google Scholar]
  23. Reese T. S., Karnovsky M. J. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol. 1967 Jul;34(1):207–217. doi: 10.1083/jcb.34.1.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Risau W., Hallmann R., Albrecht U., Henke-Fahle S. Brain induces the expression of an early cell surface marker for blood-brain barrier-specific endothelium. EMBO J. 1986 Dec 1;5(12):3179–3183. doi: 10.1002/j.1460-2075.1986.tb04627.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Stewart P. A., Wiley M. J. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail--chick transplantation chimeras. Dev Biol. 1981 May;84(1):183–192. doi: 10.1016/0012-1606(81)90382-1. [DOI] [PubMed] [Google Scholar]
  26. Tao-Cheng J. H., Nagy Z., Brightman M. W. Astrocytic orthogonal arrays of intramembranous particle assemblies are modulated by brain endothelial cells in vitro. J Neurocytol. 1990 Apr;19(2):143–153. doi: 10.1007/BF01217294. [DOI] [PubMed] [Google Scholar]
  27. Vasile E., Simionescu M., Simionescu N. Visualization of the binding, endocytosis, and transcytosis of low-density lipoprotein in the arterial endothelium in situ. J Cell Biol. 1983 Jun;96(6):1677–1689. doi: 10.1083/jcb.96.6.1677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Vlodavsky I., Fielding P. E., Fielding C. J., Gospodarowicz D. Role of contact inhibition in the regulation of receptor-mediated uptake of low density lipoprotein in cultured vascular endothelial cells. Proc Natl Acad Sci U S A. 1978 Jan;75(1):356–360. doi: 10.1073/pnas.75.1.356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Volpe J. J., Hennessy S. W., Wong T. Regulation of cholesterol ester synthesis in cultured glial and neuronal cells. Relation to control of cholesterol synthesis. Biochim Biophys Acta. 1978 Mar 30;528(3):424–435. doi: 10.1016/0005-2760(78)90032-2. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES