Abstract
1. Macromolecules cross capillary walls via large vascular pores that are thought to be formed by plasmalemmal vesicles. Early hypotheses suggested that vesicles transferred plasma constituents across the endothelial wall either by a “shuttle” mechanism or by fusing to form transient patent channels for diffusion. Recent evidence shows that the transcytotic pathway involves both movement of vesicles within the cell and a series of fusions and fissions of the vesicular and cellular membranes.
2. The transfer of macromolecules across the capillary wall is highly specific and is mediated by receptors incorporated into specific membrane domains. Therefore, despite their morphological similarity, endothelial vesicles form heterogeneous populations in which the predominant receptor proteins incorporated in their membranes define the functions of individual vesicles.
3. Blood–brain barrier capillaries have very low permeabilities to most hydrophilic molecules. Their low permeability to macromolecules has been presumed to be due to an inhibition of the transcytotic mechanism, resulting in a low density of endothelial vesicles.
4. A comparison of vesicular densities and protein permeabilities in a number of vascular beds shows only a very weak correlation, therefore vesicle numbers alone cannot be used to predict permeability to macromolecules.
5. Blood–brain barrier capillaries are fully capable of transcytosing specific proteins, for example, insulin and transferrin, although the details are still somewhat controversial.
6. It has recently been shown that the albumin binding protein gp60 (also known as albondin), which facilitates the transcytosis of native albumin in other vascular beds, is virtually absent in brain capillaries.
7. It seems likely that the low blood–brain barrier permeability to macromolecules may be due to a low level of expression of specific receptors, rather than to an inhibition of the transcytosis mechanism.
Similar content being viewed by others
REFERENCES
Balin, B. J., Broadwell, R. D., and Salcman, M. (1987). Tubular profiles do not form transendothelial channels through the blood-brain barrier. J. Neurocytol. 16:721-735.
Banks, W. A., and Broadwell, R. D. (1994). Blood to brain and brain to blood passage of native horseradish peroxidase, wheat germ agglutinin, and albumin: Pharmacokinetic and morphological assessments. J. Neurochem. 62:2404-2419.
Bearer, E. L., Orci, L., and Sors, P. (1985). Endothelial fenestral diaphragms: A quick-freeze, deepetch study. Cell Biol. 100:418-428.
Bellhorn, R. W. (1980). Permeability of blood-ocular barriers of neonatal and adult cat to sodium fluorescein. Invest. Ophthalmol. Vis. Sci. 19:870-877.
Bendayan, M., and Raskova, J. (1996). Transport of insulin and albumin by the microvascular endothelium of the rete mirabile. J. Cell Sci. 109:1857-1864.
Bent-Hansen, L. (1991). Initial plasma disappearance and tissue uptake of 131I-albumin in normal rabbits. Microvasc. Res. 41:345-356.
Bill, A. (1977). Plasma protein dynamics: albumin and IgG capillary permeability, extravascular movement and regional blood flow in unanesthetized rabbits. Acta Physiol. Scand. 101:28-42.
Broadwell, R. D. (1989). Transcytosis of macromolecules through the blood-brain barrier: A cell biological perspective and critical appraisal. Acta Neuropathol. 79:117-128.
Broadwell, R. D., Baker-Cairns, B. J., Frieden, P. M., Oliver, C., and Villegas, J. C. (1996). Transcytosis of protein through the mammalian cerebral epithelium and endothelium. III. Receptor-mediated transcytosis through the blood-brain barrier of blood-borne transferrin and antibody against the transferrin receptor. Exp. Neurol. 142:47-65.
Buchanan, R. A., Wagner, R. C., Andrews, S. B., and Frokjær-Jensen, J. (1988). Effect of section thickness on the morphological characterization of the vesicular system in endothelial cells. Microvasc. Res. 36:191-196.
Bundgaard, M. (1983). Vesicular transport in capillary endothelium: Does it occur? Fed. Proc. 42:2425-2430.
Bundgaard, M., and Frokjær-Jensen, J. (1982). Functional aspects of the ultrastructure of terminal blood vessels: A quantitative study on consecutive segments of the frog mesenteric microvasculature. Microvasc. Res. 23:1-30.
Bundgaard, M., Frokjær-Jensen, J., and Crone, C. (1979). Endothelial plasmalemmal vesicles as elements in a system of branching invaginations from the cell surface. Proc. Natl. Acad. Sci. USA 76:6439-6442.
Bundgaard, M., Hagman, P., and Crone, C. (1983). The three-dimensional organization of plasmalemmal vesicular profiles in the endothelium of rat heart capillaries. Microvasc. Res. 25:358-368.
Casley-Smith, J. R., Green, H. S., Harris, J. L., and Wadey, P. J. (1975). The quantitative morphology of skeletal muscle capillaries in relation to permeability. Microvasc. Res. 10:43-64.
Connell, C. J., and Mercer, K. L. (1974). Freeze-fracture appearance of the capillary endothelium in the cerebral cortex of mouse brain. Am. J. Anat. 140:595-599.
Coomber, B. L., and Stewart, P. A. (1985). Morphometric analysis of CNS microvascular endothelium. Microvasc. Res. 30:99-115.
Coomber, B. L., Stewart, P. A., Hayakawa, E. M., Farrell, C. L., and Del Maestro, R. F. (1988). A quantitative assessment of microvessel ultrastructure in C6 astrocytoma spheroids transplanted to brain and to muscle. J. Neuropathol. Exp. Neurol. 47:29-40.
Crowe, A., and Morgan, E. H. (1992). Iron and transferrin uptake by brain and cerebrospinal fluid in the rat. Brain Res. 592:8-16.
Cunha-Vaz, J. G., Shakib, M., and Ashton, N. (1966). Studies on the permeability of the blood-retinal barrier. 1. On the existence, development, and site of a blood-retinal barrier. Br. J. Ophthalmol. 50:441-453.
Davson, H., and Oldendorf, W. H. (1967). Transport in the central nervous system. Proc. Roy. Soc. Med. 60:326-329.
DeFouw, D. O., and Shumko, J. Z. (1986). Pulmonary microcirculation: Differences in endothelia of subpleural and alveolar capillaries. Microvasc. Res. 32:348-358.
De Paepe, M. E., Corriveau, M., Tannous, W. N., Seemayer, T. A., and Colle, E. (1992). Increased vascular permeability in pancreas of diabetic rats: Detection with high resolution protein A-gold cytochemistry. Diabetologia 35:1118-1124.
Duffy, K. R., and Pardridge, W. M. (1987). Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res. 420:32-38.
Dvorak, A. M., Kohn, S., Morgan, E. H., Fox, P., and Nagy, J. A. (1996). The vesiculo-vacuolar organelle (VV): A distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J. Leucoc. Biol. 59:100-115.
Dym, M., and Cavicchia, J. C. (1977). Further observations on the blood-testis barrier in monkeys. Biol. Reprod. 17:390-403.
Dym, M., and Fawcett, D. W. (1970). The blood-testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium. Biol. Reprod. 38:308-326.
Dziegielewska, K. M., Evans, C. A. N., Malinowska, D. H., Møllgård, K., Reynolds, M. L., and Saunders, N. R. (1980). Blood-cerebrospinal fluid transfer of plasma proteins during fetal development in the sheep. J. Physiol. 300:457-465.
Dziegielewska, K. M., Habgood, M. D., Møllgård, K., Stagaard, M., and Saunders, N. R. (1991). Speciesspecific transfer of plasma albumin from blood into different cerebrospinal fluid compartments in the fetal sheep. J. Physiol. 439:215-237.
Everett, N. B., and Simmons, B. (1958). Measurement and radioautographic localization of albumin in rat tissues after intravenous administration. Circ. Res. 6:307-313.
Fawcett, D. W., Leak, L. V., and Heidger, P. M. (1970). Electron microscopic observations on the structural components of the blood-testis barrier. J. Reprod. Fert. Suppl. 10:105-122.
Frokjær-Jensen, J. (1980). Three-dimensional organization of plasmalemmal vesicles in endothelial cells. An analysis by serial sectioning of frog mesenteric capillaries. J. Ultrastruct. Res. 73:9-20.
Frokjær-Jensen, J. (1983). The plasmalemmal vesicular system in capillary endothelium. In Mebmer, K., and Hammersen, F. (eds.), Structure and Function of Endothelial Cells. Progress in Applied Microcirculation, Vol. 1, Karger, Basel, pp. 17-34.
Frokjær-Jensen, J. (1984). The plasmalemmal vesicular system in striated muscle capillaries and in pericytes. Tissue Cell 16:31-42.
Frokjær-Jensen, J. (1990). Anatomical correlates of capillary permeability. In Molinatti, G. M., Bar, R. S., Belfiore, R., and Porta, M. (eds.), Diabetic Microangiopathy: Problems in Methodology and Clinical Aspects, Karger, Basel, pp. 28-42.
Ghinea, N., Eskenasy, M., Simionescu, M., and Simionescu, N. (1988). Identification of albumin-binding proteins in capillary endothelial cells. J. Cell Biol. 107:231-239.
Ghinea, N., Eskenasy, M., Simionescu, M., and Simionescu, N. (1989). Endothelial albumin binding proteins are membrane-associated components exposed on the cell surface. J. Biol. Chem. 264:4755-4758.
Ghitescu, L., and Bendayan, M. (1992). Transendothelial transport of serum albumin: A quantitative immunocytochemical study. J. Cell Biol. 117:745-755.
Gordon, S. R., and Essner, E. (1985). Plasma membrane-associated vesicles in retinal capillaries of the rat. Am. J. Anat. 174:161-172.
Granger, D. N., and Taylor, E. H. (1980). Permeability of intestinal capillaries to endogenous macromolecules. Am. J. Physiol. 238:H457-H464
Habgood, M. D., Sedgwick, J. E. C., Dziegielewska, K. M., and Saunders, N. R. (1992). Adevelopmentally regulated blood-cerebrospinal fluid transfer mechanism for albumin in immature rats. J. Physiol. 456:181-192.
Habgood, M. D., Knott, G. W., Dziegielewska, K. M., and Saunders, N. R. (1993). The nature of the decrease in blood-cerebrospinal fluid barrier exchange during postnatal brain development in the rat. J. Physiol. 468:73-83.
Hart, T. K., and Pino, R. M. (1986). Pseudoislet vascularization. Induction of diaphragm-fenestrated endothelia from the hepatic sinusoids. Lab. Invest. 54:304-313.
Holash, J. A., Harik, S. I., Perry, G., and Stewart, P. A. (1993). Barrier properties of testis microvessels. Proc. Natl. Acad. Sci. USA 90:11069-11073.
Horvat, R., and Palade, G. E. (1993). Thrombomodulin and thrombin localization on the vascular endothelium; Their internalization and transcytosis by plasmalemmal vesicles. Eur. J. Cell Biol. 61:299-313.
Johansson, B. R. (1979). Size and distribution of endothelial plasmalemmal vesicles in consecutive segments of the microvasculature in cat skeletal muscle. Microvasc. Res. 17:107-117.
Jones, W. R., O'Morchoe, P. J., and O'Morchoe, C. C. C. (1983). The organization of endocytotic vesicles in lymphatic endothelium. Microvasc. Res. 25:286-299.
Knott, G. W., Dziegielewska, K. M., Habgood, M. D., Li, Z., and Saunders, N. R. (1997). Albumin transfer across the choroid plexus of South American opossum (Monodelphis domestica). J. Physiol. 499:179-194.
Kvietys, P. R., Perry, M. A., and Granger, D. N. (1983). Permeability of pancreatic capillaries to small molecules. Am. J. Physiol. 245:G519-G524.
Lea, P. J. (1983). Image analysis system based on a non-dedicated microcomputer. Micron Microsc. Acta 14:301-306.
Levick, J. R., and Smaje, L. H. (1987). An analysis of the permeability of a fenestra. Microvasc. Res. 33:233-256.
McGuire, P. G., and Twietmeyer, T. A. (1983). Morphology of rapidly frozen aortic endothelial cells. Circ. Res. 53:424-429.
Mellman, I. (1996). Endocytosis and molecular sorting. Annu. Rev. Cell Dev. Biol. 12:575-625.
Milici, A. J., L'hernault, N., and Palade, G. E. (1985). Surface densities of diaphragmed fenestrae and transendothelial channels in different murine capillary beds. Circ. Res. 56:709-717.
Milici, A. J., Watrous, N. E., Stukenbrok, H., and Palade, G. E. (1987). Transcytosis of albumin in capillary endothelium. J. Cell Biol. 105:2603-2612.
Moos, T., and Mollgård, K. (1993). Cerebrovascular permeability to azo dyes and plasma proteins in rodents of different ages. Neuropathol. Appl. Neurobiol. 19:120-127.
Morioka, T., Baba, T., Black, K. L., and Streit, W. J. (1992). Inflammatory cell infiltrates vary in experimental primary and metastatic brain tumors. Neurosurgery 30:891-896.
Morris, C. M., Keith, A. B., Edwardson, J. A., and Pullen, R. G. L. (1992). Uptake and distribution of iron and transferrin in the adult rat brain. J. Neurochem. 59:300-306.
Mukherjee, S., Ghosh, R. N., and Maxfield, F. R. (1997). Endocytosis. Physiol. Rev. 77:759-800.
Nag, S. (1991). Protective effect of flunarizine on blood-brain barrier permeability alterations in acutely hypertensive rats. Stroke 22:1265-1269.
Palade, G. E. (1961). Blood capillaries of the heart and other organs. Circulation 24:368-384.
Palade, G. E., Simionescu, M., and Simionescu, N. (1979). Structural aspects of the permeability of the microvascular endothelium. Acta Physiol. Scand. 463:11-32.
Pardridge, W. M., Eisenberg, J., and Cefalu, W. T. (1985). Absence of albumin receptor on brain capillaries in vivo or in vitro. Am. J. Physiol. 249:E264-E267.
Pino, R. M. (1985). Restriction to endogenous plasma proteins by a fenestrated capillary endothelium: An ultrastructural immunocytochemical study of the choriocapillary endothelium. Am. J. Anat. 172:279-289.
Pino, R. M., and Essner, E. (1993). Structure and permeability to ferritin of the choriocapillary endothelium of the rat eye. Cell Tissue Res. 208:21-27.
Powers, R. W., Chen, L., Russell, P. T., and Larsen, W. J. (1995). Gonadotropin-stimulated regulation of blood-follicle barrier is mediated by nitric oxide. Am. J. Physiol. 269:E290-E298.
Predescu, D. N., Horvat, R., Predescu, S. A., and Palade, G. E. (1994). Transcytosis in the continuous endothelium of the myocardial microvasculature is inhibited by N-ethylmaleimide. Proc. Natl. Acad. Sci. USA 91:3014-3018.
Raviola, G., and Butler, J. M. (1984). Unidirectional transport mechanism of horseradish peroxidase in the vessels of the iris. Invest. Ophthalmol. Vis. Sci. 25:827-836.
Reese, T. S., and Karnovsky, M. J. (1967). Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34:207-217.
Roberts, R., Sandra, A., Siek, G. C., Lucas, J. J., and Fine, R. E. (1992). Studies of the mechanism of iron transport across the blood-brain barrier. Ann. Neurol. 32 (Suppl.):S43-S50.
Roberts, R. L., Fine, R. E., and Sandra, A. (1993). Receptor-mediated endocytosis of transferrin at the blood-brain barrier. J. Cell Sci. 104:521-532.
Sadasivudu, B., Murthy, C. R. K., Roa, G. N., and Swamy, M. (1983). Studies on acetylcholinesterase and gamma-glutamyltranspeptidase in mouse brain in ammonia toxicity. J. Neurosci. Res. 9:127-134.
Schnitzer, J. E. (1992). gp60 is an albumin-binding glycoprotein expressed by continuous endothelium involved in albumin transcytosis. Am. J. Physiol. 262:H246-H254.
Schnitzer, J. E., and Oh, P. (1994). Albondin-mediated capillary permeability to albumin. Differential role of receptors in endothelial transcytosis and endocytosis of native and modified albumins. J. Biol. Chem. 269:6072-6082.
Schnitzer, J., Oh, P., Pinney, E., and Allard, J. (1994). Filipin-sensitive caveolae-mediated transport in endothelium: Reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. J. Cell Biol. 127:1217-1232.
Schnitzer, J. E., Allard, J., and Oh, P. (1995). NEM inhibits transcytosis, endocytosis, and capillary permeability: Implication of caveolae fusion in endothelia. Am. J. Physiol. 268:H48-H55.
Schwartz, M. W., Sipols, A., Kahn, S. E., Lattemann, D. F., Taborsky, G. J., Jr., Bergman, R. N., Woods, S. C., and Porte, D., Jr. (1990). Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am. J. Physiol. Endocrinol. Metab. 259:E378-E383.
Sejrsen, P., Paaske, W. P., and Henriksen, O. (1985). Capillary permeability of 131I-albumin in skeletal muscle. Microvasc. Res. 29:265-281.
Setchell, B. P., Pöllänen, P., and Zupp, J. L. (1988). Development of the blood-testis barrier and changes in vascular permeability at puberty in rats. Int. J. Androl. 11:225-253.
Simionescu, M., Simionescu, N., and Palade, G. E. (1974). Morphometric data on the endothelium of blood capillaries. J. Cell Biol. 60:128-152.
Simionescu, N., Simionescu, M., and Palade, G. E. (1975). Permeability of muscle capillaries to small heme-peptides. Evidence for the existence of patent transendothelial channels. J. Cell Biol. 64:586-607.
Simionescu, N., Simionescu, M., and Palade, G. E. (1978). Structural basis of permeability in sequential segments of the microvasculature of the diaphragm. II. Pathways followed by microperoxidase across the endothelium. Microvasc. Res. 15:17-36.
Smith, R. S., and Rudt, L. A. (1975). Ocular vascular and epithelial barriers to microperoxidase. Invest. Ophthalmol. Vis. Sci. 14:556-560.
Stewart, P. A., and Hayakawa, K. (1994). Early ultrastructural changes in blood-brain barrier vessels of the rat embryo. Dev. Brain Res. 78:25-34.
Stewart, P. A., and Tuor, U. I. (1994). Blood-eye barriers in the rat: Correlation of ultrastructure with function. J. Comp. Neurol. 340:566-576.
Stewart, P. A., Hayakawa, K., Hayakawa, E. M., Farrell, C. L., and Del Maestro, R. F. (1985). A quantitative study of blood-brain barrier permeability ultrastructure in a new rat glioma model. Acta Neuropathol. 67:96-102.
Stewart, P. A., Magliocco, M., Hayakawa, K., Farrell, C. L., Del Maestro, R. F., Girvin, J., Kaufmann, J. C. E., Vinters, H. V., and Gilbert, J. J. (1987). A quantitative analysis of blood-brain barrier ultrastructure in the aging human. Microvasc. Res. 33:270-282.
Stewart, P. A., Farrell, C. R., Farrell, C. L., and Hayakawa, E. M. (1992). Horseradish peroxidase retention and washout in blood-brain barrier lesions. J. Neurosci. Methods 41:75-84.
Stewart, P. A., Isaacs, H., LaManna, J. C., and Harik, S. I. (1997). Ultrastructural concomitants of hypoxia-induced angiogenesis. Acta Neuropathol. 93:579-584.
Svendsen, J. H., Paaske, W. P., Sejrsen, P., and Haunsø, S. (1989). Capillary permeability of 131Ialbumin in canine myocardium as determined by bolus injection, residue detection. Microvasc. Res. 37:352-356.
Szalay, J., Nunziata, B., and Henkind, P. (1975). Permeability of iridial blood vessels. Exp. Eye Res. 21:531-543.
Tiruppathi, C., Finnegan, A., and Malik, A. B. (1996). Isolation and characterization of a cell surface albumin-binding protein from vascular endothelial cells. Proc. Natl. Acad. Sci. USA 93:250-254.
Villegas, J. C., and Broadwell, R. D. (1993). Transcytosis of protein through the mammalian cerebral epithelium and endothelium. 11. Adsorptive transcytosis of WGA-HRP and the blood-brain and brain-blood barriers. J. Neurocytol. 22:67-80.
Vorbrodt, A. W., and Dobrogowska, D. H. (1994). Immunocytochemical evaluation of blood-brain barrier to endogenous albumin in adult, newborn and aged mice. Folia Histochem. Cytobiol. 32:63-70.
Vorbrodt, A. W., Dobrogowska, D. H., and Lossinsky, A. S. (1994). Ultrastructural study on the interaction of insulin-albumin-gold complex with mouse brain microvascular endothelial cells. J. Neurocytol. 23:201-208.
Wagner, R. C. (1984). Application of high voltage electron microscopy to visualize the three-dimensional structure of the vesicular system in thick sections. Int. J. Microcirc. Clin. Exp. 3:413-413.
Wagner, R. C., and Andrews, S. B. (1985). Ultrastructure of the vesicular system in rapidly frozen capillary endothelium of the rete mirabile. J. Ultrastruct. Res. 90:172.
Wagner, R. C., and Casley-Smith, J. R. (1981). The quantitative morphometry of capillaries isolated from fat. Microcirculation 1:177-197.
Wagner, R. C., and Robinson, C. S. (1982). Tannic acid tracer analysis of permeability pathways in the capillaries of the rete mirabile: Demonstration of the discreteness of endothelial vesicles. J. Ultrastruct. Res. 81:37-46.
Wagner, R. C., and Robinson, C. S. (1984). High-voltage electron microscopy of capillary endothelial vesicles. Microvasc. Res. 28:197-205.
Weibel, E. R. (1979). Stereological Methods, Vol. 1. Practical Methods for Biological Morphometry, 1st ed., Academic Press, Toronto.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stewart, P.A. Endothelial Vesicles in the Blood–Brain Barrier: Are They Related to Permeability?. Cell Mol Neurobiol 20, 149–163 (2000). https://doi.org/10.1023/A:1007026504843
Issue Date:
DOI: https://doi.org/10.1023/A:1007026504843