Abstract
Endothelial cells are covered with a polysaccharide rich layer more than 400 nm thick, mechanical properties of which limit access of circulating plasma components to endothelial cell membranes. The barrier properties of this endothelial surface layer are deduced from the rate of tracer penetration into the layer and the mechanics of red and white cell movement through capillary microvessels. This review compares the mechanosensor and permeability properties of an inner layer (100–150 nm, close to the endothelial membrane) characterized as a quasi-periodic structure which accounts for key aspects of transvascular exchange and vascular permeability with those of the whole endothelial surface layers. We conclude that many of the barrier properties of the whole surface layer are not representative of the primary fiber matrix forming the molecular filter determining transvascular exchange. The differences between the properties of the whole layer and the inner glycocalyx structures likely reflect dynamic aspects of the endothelial surface layer including tracer binding to specific components, synthesis and degradation of key components, activation of signaling pathways in the endothelial cells when components of the surface layer are lost or degraded, and the spatial distribution of adhesion proteins in microdomains of the endothelial cell membrane.
Similar content being viewed by others
References
Adamson, R. H., and G. Clough. Plasma proteins modify the endothelial cell glycocalyx of frog mesenteric microvessels. J. Physiol. 445:473–486, 1992.
Adamson, R. H., J. F. Lenz, X. Zhang, G. N. Adamson, S. Weinbaum, F. E. Curry, et al. Oncotic pressures opposing filtration across non-fenestrated rat microvessels. J. Physiol. 557:889–907, 2004.
Adamson, R. H., R. K. Sarai, S. Weinbaum, and F. E. Curry. Retrograde shear stress modulates rat mesentery microvessel permeability and endothelial adhesion structures. FASEB J. 23:950–955, 2010.
Arkill, K. P., C. Knupp, C. C. Michel, C. R. Neal, K. Qvortrup, J. Rostgaard, and J. M. Squire. Similar endothelial glycocalyx structures in microvessels from a range of Mammalian tissues: evidence for a common filtering mechanism? Biophys. J. 101:1046–1056, 2011.
Becker, B. F., D. Chappell, D. Bruegger, T. Annecke, and M. Jacob. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc. Res. 87:300–310, 2010.
Broekhuizen, L. N., B. A. Lemkes, H. L. Mooij, M. C. Meuwese, H. Verberne, F. Holleman, R. O. Schlingemann, M. Nieuwdorp, E. S. Stroes, and H. Vink. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia 53:2646–2655, 2010.
Bruegger, D., M. Rehm, J. Abicht, J. O. Paul, M. Stoeckelhuber, M. Pfirrmann, B. Reichart, B. F. Becker, and F. Christ. Shedding of the endothelial glycocalyx during cardiac surgery: on-pump versus off-pump coronary artery bypass graft surgery. J. Thorac. Cardiovasc. Surg. 138:1445–1447, 2009.
Chappell, D., K. Hofmann-Kiefer, M. Jacob, M. Rehm, J. Briegel, U. Welsch, P. Conzen, and B. F. Becker. TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res. Cardiol. 104:78–89, 2009.
Chappell, D., M. Jacob, O. Paul, M. Rehm, U. Welsch, M. Stoeckelhuber, P. Conzen, and B. F. Becker. The glycocalyx of the human umbilical vein endothelial cell: an impressive structure ex vivo but not in culture. Circ. Res. 104:1313–1317, 2009.
Clough, G., and C. C. Michel. The role of vesicles in the transport of ferritin through frog endothelium. J. Physiol. 315:127–142, 1981.
Clough, G., C. C. Michel, and M. E. Phillips. Inflammatory changes in permeability and ultrastructure of single vessels in the frog mesenteric microcirculation. J. Physiol. 395:99–114, 1988.
Constantinescu, A. A., H. Vink, and J. A. Spaan. Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler. Thromb. Vasc. Biol. 23:1541–1547, 2003.
Curry, F. R., and R. H. Adamson. Vascular permeability modulation at the cell, microvessel, or whole organ level: towards closing gaps in our knowledge. Cardiovasc. Res. 87:218–229, 2010.
Curry, F. E., and C. C. Michel. A fiber matrix model of capillary permeability. Microvasc. Res. 20:96–99, 1980.
Desjardins, C., and B. R. Duling. Heparinase treatment suggests a role for the endothelial cell glycocalyx in regulation of capillary hematocrit. Am. J. Physiol. 258:H647–H654, 1990.
Ebong, E. E., F. P. Macaluso, D. C. Spray, and J. M. Tarbell. Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler. Thromb. Vasc. Biol. 31(8):1908–1915, 2011.
Feng, J., and S. Weinbaum. Lubrication theory in highly compressible porous media: the mechanics of skiing, from red cells to humans. J. Fluid Mech. 422:281–317, 2000.
Florian, J. A., J. R. Kosky, K. Ainslie, Z. Pang, R. O. Dull, and J. M. Tarbell. Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ. Res. 93:e136–e142, 2003.
Forsyth, A. M., J. Wan, P. D. Owrutsky, M. Abkarian, and H. A. Stone. Multiscale approach to link red blood cell dynamics, shear viscosity, and ATP release. Proc. Natl. Acad. Sci. USA 108:10986–10991, 2011.
Gao, L., and H. H. Lipowsky. Composition of the endothelial glycocalyx and its relation to its thickness and diffusion of small solutes. Microvasc. Res. 80:394–401, 2010.
Giantsos, K. M., P. Kopeckova, and R. O. Dull. The use of an endothelium-targeted cationic copolymer to enhance the barrier function of lung capillary endothelial monolayers. Biomaterials 30:5885–5891, 2009.
Giantsos-Adams, K., V. Lopez-Quintero, P. Kopeckova, J. Kopecek, J. M. Tarbell, and R. Dull. Study of the therapeutic benefit of cationic copolymer administration to vascular endothelium under mechanical stress. Biomaterials 32:288–294, 2011.
Gopalan, P. K., A. R. Burns, S. I. Simon, S. Sparks, L. V. McIntire, and C. W. Smith. Preferential sites for stationary adhesion of neutrophils to cytokine-stimulated HUVEC under flow conditions. J. Leukoc. Biol. 68:47–57, 2000.
Gouverneur, M., J. A. Spaan, H. Pannekoek, R. D. Fontijn, and H. Vink. Fluid shear stress stimulates incorporation of hyaluronan into endothelial cell glycocalyx. Am. J. Physiol. Heart Circ. Physiol. 290:H458–H462, 2006.
Gudi, S., I. Huvar, C. R. White, N. L. McKnight, N. Dusserre, G. R. Boss, and J. A. Frangos. Rapid activation of Ras by fluid flow is mediated by Galpha(q) and Gbetagamma subunits of heterotrimeric G proteins in human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 23:994–1000, 2003.
He, P., and F. E. Curry. Albumin modulation of capillary permeability: role of endothelial cell [Ca2+]i. Am. J. Physiol. 265:H74–H82, 1993.
He, P., J. Wang, and M. Zeng. Leukocyte adhesion and microvessel permeability. Am. J. Physiol. Heart Circ. Physiol. 278:H1686–H1694, 2000.
Henry, C. B., and B. R. Duling. Permeation of the luminal capillary glycocalyx is determined by hyaluronan. Am. J. Physiol. 277:H508–H514, 1999.
Henry, C. B., and B. R. Duling. TNF-alpha increases entry of macromolecules into luminal endothelial cell glycocalyx. Am. J. Physiol. Heart Circ. Physiol. 279:H2815–H2823, 2000.
Hierck, B. P., K. Van der Heiden, F. E. Alkemade, S. Van de Pas, J. V. Van Thienen, B. C. Groenendijk, W. H. Bax, A. Van der Laarse, M. C. Deruiter, A. J. Horrevoets, R. E. Poelmann, et al. Primary cilia sensitize endothelial cells for fluid shear stress. Dev. Dyn. 237:725–735, 2008.
Hu, X., and S. Weinbaum. A new view of Starling’s hypothesis at the microstructural level. Microvasc. Res. 58:281–304, 1999.
Huxley, V. H., and F. E. Curry. Albumin modulation of capillary permeability: test of an adsorption mechanism. Am. J. Physiol. 248:H264–H273, 1985.
Huxley, V. H., and D. A. Williams. Role of a glycocalyx on coronary arteriole permeability to proteins: evidence from enzyme treatments. Am. J. Physiol. Heart Circ. Physiol. 278:H1177–H1185, 2000.
Jacob, R. Agonist-stimulated divalent cation entry into single cultured human umbilical vein endothelial cells. J. Physiol. 421:55–77, 1990.
Jalali, S., M. A. del Pozo, K. Chen, H. Miao, Y. Li, M. A. Schwartz, J. Y. Shyy, and S. Chien. Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands. Proc. Natl. Acad. Sci. USA 98:1042–1046, 2001.
Kajimura, M., and C. C. Michel. Flow modulates the transport of K+ through the walls of single perfused mesenteric venules in anaesthetised rats. J. Physiol. 521(Pt 3):665–677, 1999.
Kim, M. H., N. R. Harris, and J. M. Tarbell. Regulation of capillary hydraulic conductivity in response to an acute change in shear. Am. J. Physiol. Heart Circ. Physiol. 289:H2126–H2135, 2005.
Laurent, T. C., and J. R. Fraser. Hyaluronan. FASEB J. 6:2397–2404, 1992.
Levick, J. R., and C. C. Michel. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87:198–210, 2010.
Lopez-Quintero, S. V., R. Amaya, M. Pahakis, and J. M. Tarbell. The endothelial glycocalyx mediates shear-induced changes in hydraulic conductivity. Am. J. Physiol. Heart Circ. Physiol. 296:H1451–H1456, 2009.
Luft, J. H. Fine structures of capillary and endocapillary layer as revealed by ruthenium red. Fed. Proc. 25:1773–1783, 1966.
Marechal, X., R. Favory, O. Joulin, D. Montaigne, S. Hassoun, B. Decoster, F. Zerimech, and R. Neviere. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock 29:572–576, 2008.
Melchior, B., and J. A. Frangos. Shear-induced endothelial cell–cell junction inclination. Am. J. Physiol. Cell Physiol. 299:C621–C629, 2010.
Michel, C. C. Capillary permeability and how it may change. J. Physiol. 404:1–29, 1988.
Michel, C. C., and F. E. Curry. Microvascular permeability. Physiol. Rev. 79:703–761, 1999.
Mulivor, A. W., and H. H. Lipowsky. Inhibition of glycan shedding and leukocyte–endothelial adhesion in postcapillary venules by suppression of matrixmetalloprotease activity with doxycycline. Microcirculation 16:657–666, 2009.
Muller, W. A. Mechanisms of transendothelial migration of leukocytes. Circ. Res. 105:223–230, 2009.
Neal, C. R., and D. O. Bates. Measurement of hydraulic conductivity of single perfused Rana mesenteric microvessels between periods of controlled shear stress. J. Physiol. 543:947–957, 2002.
Nieuwdorp, M., M. C. Meuwese, H. L. Mooij, M. H. van Lieshout, A. Hayden, M. Levi, J. C. Meijers, C. Ince, J. J. Kastelein, H. Vink, and E. S. Stroes. Tumor necrosis factor-alpha inhibition protects against endotoxin-induced endothelial glycocalyx perturbation. Atherosclerosis 202:296–303, 2009.
Nieuwdorp, M., H. L. Mooij, J. Kroon, B. Atasever, J. A. Spaan, C. Ince, F. Holleman, M. Diamant, R. J. Heine, J. B. Hoekstra, J. J. Kastelein, E. S. Stroes, and H. Vink. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55:1127–1132, 2006.
Nieuwdorp, M., T. W. van Haeften, M. C. Gouverneur, H. L. Mooij, M. H. van Lieshout, M. Levi, J. C. Meijers, F. Holleman, J. B. Hoekstra, H. Vink, J. J. Kastelein, and E. S. Stroes. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55:480–486, 2006.
Noble, M. I., A. J. Drake-Holland, and H. Vink. Hypothesis: arterial glycocalyx dysfunction is the first step in the atherothrombotic process. QJM 101:513–518, 2008.
Ogston, A. G. The spaces in a uniform random suspension of fibres. Trans. Faraday Soc. 54:1754–1757, 1958.
Ogston, A. G., and C. C. Michel. General descriptions of passive transport of neutral solute and solvent through membranes. Prog. Biophys. Mol. Biol. 34:197–217, 1978.
Perrin, R. M., S. J. Harper, and D. O. Bates. A role for the endothelial glycocalyx in regulating microvascular permeability in diabetes mellitus. Cell Biochem. Biophys. 49:65–72, 2007.
Platts, S. H., and B. R. Duling. Adenosine A3 receptor activation modulates the capillary endothelial glycocalyx. Circ. Res. 94:77–82, 2004.
Potter, D. R., and E. R. Damiano. The hydrodynamically relevant endothelial cell glycocalyx observed in vivo is absent in vitro. Circ. Res. 102:770–776, 2008.
Pries, A. R., and W. M. Kuebler. Normal endothelium. Handb. Exp. Pharmacol. 1–40, 2006.
Pries, A. R., T. W. Secomb, H. Jacobs, M. Sperandio, K. Osterloh, and P. Gaehtgens. Microvascular blood flow resistance: role of endothelial surface layer. Am. J. Physiol. 273:H2272–H2279, 1997.
Rehm, M., D. Bruegger, F. Christ, P. Conzen, M. Thiel, M. Jacob, D. Chappell, M. Stoeckelhuber, U. Welsch, B. Reichart, K. Peter, and B. F. Becker. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 116:1896–1906, 2007.
Rehm, M., M. Haller, V. Orth, U. Kreimeier, M. Jacob, H. Dressel, S. Mayer, H. Brechtelsbauer, and U. Finsterer. Changes in blood volume and hematocrit during acute preoperative volume loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy. Anesthesiology 95:849–856, 2001.
Reitsma, S., D. W. Slaaf, H. Vink, M. A. van Zandvoort, and M. G. oude Egbrink. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 454:345–359, 2007.
Renkin, E. M., and F. E. Curry. Transport of water and solutes across capillary endothelium. In: Membrane Transport in Physiology, edited by G. Giebisch, D. C. Tosteson, and H. H. Ussing. Heidelberg: Springer, 1978, pp. 1–45.
Rostgaard, J., and K. Qvortrup. Electron microscopic demonstrations of filamentous molecular sieve plugs in capillary fenestrae. Microvasc. Res. 53:1–13, 1997.
Rostgaard, J., and K. Qvortrup. Sieve plugs in fenestrae of glomerular capillaries—site of the filtration barrier? Cells Tissues Organs 170:132–138, 2002.
Secomb, T. W., R. Hsu, and A. R. Pries. Motion of red blood cells in a capillary with an endothelial surface layer: effect of flow velocity. Am. J. Physiol. Heart Circ. Physiol. 281:H629–H636, 2001.
Simon, S. I., M. R. Sarantos, C. E. Green, and U. Y. Schaff. Leukocyte recruitment under fluid shear: mechanical and molecular regulation within the inflammatory synapse. Clin. Exp. Pharmacol. Physiol. 36:217–224, 2009.
Singleton, P. A., S. M. Dudek, S. F. Ma, and J. G. Garcia. Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. J. Biol. Chem. 281:34381–34393, 2006.
Sperandio, M., C. A. Gleissner, and K. Ley. Glycosylation in immune cell trafficking. Immunol. Rev. 230:97–113, 2009.
Squire, J. M., M. Chew, G. Nneji, C. Neal, J. Barry, and C. Michel. Quasi-periodic substructure in the microvessel endothelial glycocalyx: a possible explanation for molecular filtering? J. Struct. Biol. 136:239–255, 2001.
Stevens, A. P., V. Hlady, and R. O. Dull. Fluorescence correlation spectroscopy can probe albumin dynamics inside lung endothelial glycocalyx. Am. J. Physiol. Lung Cell. Mol. Physiol. 293:L328–L335, 2007.
Sumagin, R., J. M. Kuebel, and I. H. Sarelius. Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1. Am. J. Physiol. Cell Physiol. 301(4):C777–C779, 2011.
Tarbell, J. M. Shear stress and the endothelial transport barrier. Cardiovasc. Res. 87:320–330, 2010.
Tarbell, J. M., and M. Y. Pahakis. Mechanotransduction and the glycocalyx. J. Intern. Med. 259:339–350, 2006.
Thi, M. M., J. M. Tarbell, S. Weinbaum, and D. C. Spray. The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: a “bumper-car” model. Proc. Natl. Acad. Sci. USA 101:16483–16488, 2004.
Trung, D. T., and B. Wills. Systemic vascular leakage associated with dengue infections—the clinical perspective. Curr. Top. Microbiol. Immunol. 338:57–66, 2010.
Turner, M. R., G. Clough, and C. C. Michel. The effects of cationised ferritin and native ferritin upon the filtration coefficient of single frog capillaries. Evidence that proteins in the endothelial cell coat influence permeability. Microvasc. Res. 25:205–222, 1983.
Tzima, E., M. Irani-Tehrani, W. B. Kiosses, E. Dejana, D. A. Schultz, B. Engelhardt, G. Cao, H. DeLisser, and M. A. Schwartz. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431, 2005.
van den Berg, B. M., H. Vink, and J. A. Spaan. The endothelial glycocalyx protects against myocardial edema. Circ. Res. 92:592–594, 2003.
van Haaren, P. M., E. VanBavel, H. Vink, and J. A. Spaan. Localization of the permeability barrier to solutes in isolated arteries by confocal microscopy. Am. J. Physiol. Heart Circ. Physiol. 285:H2848–H2856, 2003.
VanTeeffelen, J. W., J. Brands, and H. Vink. Agonist-induced impairment of glycocalyx exclusion properties: contribution to coronary effects of adenosine. Cardiovasc. Res. 87:311–319, 2010.
VanTeeffelen, J. W., A. A. Constantinescu, J. Brands, J. A. Spaan, and H. Vink. Bradykinin- and sodium nitroprusside-induced increases in capillary tube haematocrit in mouse cremaster muscle are associated with impaired glycocalyx barrier properties. J. Physiol. 586:3207–3218, 2008.
Vink, H., A. A. Constantinescu, and J. A. Spaan. Oxidized lipoproteins degrade the endothelial surface layer: implications for platelet–endothelial cell adhesion. Circulation 101:1500–1502, 2000.
Vink, H., and B. R. Duling. Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ. Res. 79:581–589, 1996.
Vink, H., and B. R. Duling. Capillary endothelial surface layer selectively reduces plasma solute distribution volume. Am. J. Physiol. Heart Circ. Physiol. 278:H285–H289, 2000.
Weinbaum, S., J. M. Tarbell, and E. R. Damiano. The structure and function of the endothelial glycocalyx layer. Annu. Rev. Biomed. Eng. 9:121–167, 2007.
Weinbaum, S., X. Zhang, Y. Han, H. Vink, and S. C. Cowin. Mechanotransduction and flow across the endothelial glycocalyx. Proc. Natl. Acad. Sci. USA 100:7988–7995, 2003.
Werthmann, R. C., M. J. Lohse, and M. Bunemann. Temporally resolved cAMP monitoring in endothelial cells uncovers a thrombin-induced [cAMP] elevation mediated via the Ca(2)+-dependent production of prostacyclin. J. Physiol. 589:181–193, 2011.
Williams, D. A. A shear stress component to the modulation of capillary hydraulic conductivity (Lp). Microcirculation 3:229–232, 1996.
Wojciechowski, J. C., and I. H. Sarelius. Preferential binding of leukocytes to the endothelial junction region in venules in situ. Microcirculation 12:349–359, 2005.
Xu, D., T. L. Wang, L. P. Sun, and Q. D. You. Recent progress of small molecular VEGFR inhibitors as anticancer agents. Mini Rev. Med. Chem. 11:18–31, 2011.
Yao, Y., A. Rabodzey, and C. F. Dewey, Jr. Glycocalyx modulates the motility and proliferative response of vascular endothelium to fluid shear stress. Am. J. Physiol. Heart Circ. Physiol. 293:H1023–H1030, 2007.
Yu, J., S. Bergaya, T. Murata, I. F. Alp, M. P. Bauer, M. I. Lin, M. Drab, T. V. Kurzchalia, R. V. Stan, and W. C. Sessa. Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels. J. Clin. Invest. 116:1284–1291, 2006.
Yuan, Y., H. J. Granger, D. C. Zawieja, and W. M. Chilian. Flow modulates coronary venular permeability by a nitric oxide-related mechanism. Am. J. Physiol. 263:H641–H646, 1992.
Zeng, M., H. Zhang, C. Lowell, and P. He. Tumor necrosis factor-alpha-induced leukocyte adhesion and microvessel permeability. Am. J. Physiol. Heart Circ. Physiol. 283:H2420–H2430, 2002.
Zhang, X., R. H. Adamson, F. E. Curry, and S. Weinbaum. Transient regulation of transport by pericytes in venular microvessels via trapped microdomains. Proc. Natl. Acad. Sci. USA 105:1374–1379, 2008.
Acknowledgments
This study is supported by the NIH HL28607 and the HL44485. The authors thank Prof. Scott I. Simon for permitting the use of the illustration in Fig. 3a.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Scott I. Simon oversaw the review of this article.
Rights and permissions
About this article
Cite this article
Curry, F.E., Adamson, R.H. Endothelial Glycocalyx: Permeability Barrier and Mechanosensor. Ann Biomed Eng 40, 828–839 (2012). https://doi.org/10.1007/s10439-011-0429-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-011-0429-8