The endothelial glycocalyx and its disruption, protection and regeneration: a narrative review

Danielli JF. Capillary permeability and oedema in the perfused frog. J Physiol. 1940;98(1):109–29.

Luft JH. Fine structures of capillary and endocapillary layer as revealed by ruthenium red. Fed Proc. 1966;25(6):1773–83.

Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch. 2000;440(5):653–66.

Chelazzi C, Villa G, Mancinelli P, De Gaudio AR, Adembri C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit Care. 2015;19:26.

Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345–59.

Li L, Ly M, Linhardt RJ. Proteoglycan sequence. Mol Biosyst. 2012;8(6):1613–25.

Ueda A, Shimomura M, Ikeda M, Yamaguchi R, Tanishita K. Effect of glycocalyx on shear-dependent albumin uptake in endothelial cells. Am J Physiol Heart Circ Physiol. 2004;287(5):H2287–94.

Rehm M, Zahler S, Lotsch M, Welsch U, Conzen P, Jacob M, et al. Endothelial glycocalyx as an additional barrier determining extravasation of 6 % hydroxyethyl starch or 5 % albumin solutions in the coronary vascular bed. Anesthesiology. 2004;100(5):1211–23.

Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes. 2006;55(2):480–6.

Alphonsus CS, Rodseth RN. The endothelial glycocalyx: a review of the vascular barrier. Anaesthesia. 2014;69(7):777–84.

Bansch P, Nelson A, Ohlsson T, Bentzer P. Effect of charge on microvascular permeability in early experimental sepsis in the rat. Microvasc Res. 2011;82(3):339–45.

Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007;116(17):1896–906.

Henry CB, Duling BR. Permeation of the luminal capillary glycocalyx is determined by hyaluronan. Am J Physiol. 1999;277(2 Pt 2):H508–14.

Lipowsky HH, Gao L, Lescanic A. Shedding of the endothelial glycocalyx in arterioles, capillaries, and venules and its effect on capillary hemodynamics during inflammation. Am J Physiol Heart Circ Physiol. 2011;301(6):H2235–45.

Constantinescu AA, Vink H, Spaan JA. Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler Thromb Vasc Biol. 2003;23(9):1541–7.

Vink H, Duling BR. Capillary endothelial surface layer selectively reduces plasma solute distribution volume. Am J Physiol Heart Circ Physiol. 2000;278(1):H285–9.

Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM. Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res. 2003;93(10):e136–42.

Kolarova H, Ambruzova B, Svihalkova Sindlerova L, Klinke A, Kubala L. Modulation of endothelial glycocalyx structure under inflammatory conditions. Mediators Inflamm. 2014;2014:694312.

Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br J Clin Pharmacol. 2015;80(3):389–402.

Yen W, Cai B, Yang J, Zhang L, Zeng M, Tarbell JM, et al. Endothelial surface glycocalyx can regulate flow-induced nitric oxide production in microvessels in vivo. PLoS One. 2015;10(1):e0117133.

Biddle C. Like a slippery fish, a little slime is a good thing: the glycocalyx revealed. AANA J. 2013;81(6):473–80.

Henry CB, Duling BR. TNF-alpha increases entry of macromolecules into luminal endothelial cell glycocalyx. Am J Physiol Heart Circ Physiol. 2000;279(6):H2815–23.

Bruegger D, Jacob M, Rehm M, Loetsch M, Welsch U, Conzen P, et al. Atrial natriuretic peptide induces shedding of endothelial glycocalyx in coronary vascular bed of guinea pig hearts. Am J Physiol Heart Circ Physiol. 2005;289(5):H1993–9.

Gouverneur M, Spaan JA, Pannekoek H, Fontijn RD, Vink H. Fluid shear stress stimulates incorporation of hyaluronan into endothelial cell glycocalyx. Am J Physiol Heart Circ Physiol. 2006;290(1):H458–2.

Subramanian SV, Fitzgerald ML, Bernfield M. Regulated shedding of syndecan-1 and −4 ectodomains by thrombin and growth factor receptor activation. J Biol Chem. 1997;272(23):14713–20.

Zuurbier CJ, Demirci C, Koeman A, Vink H, Ince C. Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells. J Appl Physiol (1985). 2005;99(4):1471–6.

Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289–95.

Torres LN, Sondeen JL, Ji L, Dubick MA, Torres FI. Evaluation of resuscitation fluids on endothelial glycocalyx, venular blood flow, and coagulation function after hemorrhagic shock in rats. J Trauma Acute Care Surg. 2013;75(5):759–66.

Mulivor AW, Lipowsky HH. Inflammation- and ischemia-induced shedding of venular glycocalyx. Am J Physiol Heart Circ Physiol. 2004;286(5):H1672–80.

Sillesen M, Rasmussen LS, Jin G, Jepsen CH, Imam A, Hwabejire JO, et al. Assessment of coagulopathy, endothelial injury, and inflammation after traumatic brain injury and hemorrhage in a porcine model. J Trauma Acute Care Surg. 2014;76(1):12–9.

Chappell D, Bruegger D, Potzel J, Jacob M, Brettner F, Vogeser M, et al. Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx. Crit Care. 2014;18(5):538.

Koning NJ, Vonk AB, Vink H, Boer C. Side-by-side alterations in glycocalyx thickness and perfused microvascular density during acute microcirculatory alterations in cardiac surgery. Microcirculation. 2016;23(1):69–74.

Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg. 2011;254(2):194–200.

Nelson A, Berkestedt I, Bodelsson M. Circulating glycosaminoglycan species in septic shock. Acta Anaesthesiol Scand. 2014;58(1):36–43.

Rahbar E, Cardenas JC, Baimukanova G, Usadi B, Bruhn R, Pati S, et al. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J Transl Med. 2015;13:117.

Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60–6.

Johansen ME, Johansson PI, Ostrowski SR, Bestle MH, Hein L, Jensen AL, et al. Profound endothelial damage predicts impending organ failure and death in sepsis. Semin Thromb Hemost. 2015;41(1):16–25.

Neves FM, Meneses GC, Sousa NE, Menezes RR, Parahyba MC, Martins AM, et al. Syndecan-1 in acute decompensated heart failure--association with renal function and mortality. Circ J. 2015;79(7):1511–9.

Zeng Y, Adamson RH, Curry FR, Tarbell JM. Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding. Am J Physiol Heart Circ Physiol. 2014;306(3):H363–72.

Zeng Y, Liu XH, Tarbell J, Fu B. Sphingosine 1-phosphate induced synthesis of glycocalyx on endothelial cells. Exp Cell Res. 2015;339(1):90–5.

Chappell D, Jacob M, Hofmann-Kiefer K, Bruegger D, Rehm M, Conzen P, et al. Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Anesthesiology. 2007;107(5):776–84.

Chappell D, Jacob M, Hofmann-Kiefer K, Rehm M, Welsch U, Conzen P, et al. Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc Res. 2009;83(2):388–96.

Chappell D, Hofmann-Kiefer K, Jacob M, Rehm M, Briegel J, Welsch U, et al. TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol. 2009;104(1):78–89.

Chappell D, Dorfler N, Jacob M, Rehm M, Welsch U, Conzen P, et al. Glycocalyx protection reduces leukocyte adhesion after ischemia/reperfusion. Shock. 2010;34(2):133–9.

Bruegger D, Rehm M, Jacob M, Chappell D, Stoeckelhuber M, Welsch U, et al. Exogenous nitric oxide requires an endothelial glycocalyx to prevent postischemic coronary vascular leak in guinea pig hearts. Crit Care. 2008;12(3):R73.

Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF. Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular permeability. Anesthesiology. 2006;104(6):1223–31.

Jacob M, Paul O, Mehringer L, Chappell D, Rehm M, Welsch U, et al. Albumin augmentation improves condition of guinea pig hearts after 4 h of cold ischemia. Transplantation. 2009;87(7):956–65.

Haywood-Watson RJ, Holcomb JB, Gonzalez EA, Peng Z, Pati S, Park PW, et al. Modulation of syndecan-1 shedding after hemorrhagic shock and resuscitation. PLoS One. 2011;6(8):e23530.

Mulivor AW, Lipowsky HH. Inhibition of glycan shedding and leukocyte-endothelial adhesion in postcapillary venules by suppression of matrixmetalloprotease activity with doxycycline. Microcirculation. 2009;16(8):657–66.

Marechal X, Favory R, Joulin O, Montaigne D, Hassoun S, Decoster B, et al. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock. 2008;29(5):572–6.

Eskens BJ, Zuurbier CJ, van Haare J, Vink H, van Teeffelen JW. Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice. Cardiovasc Diabetol. 2013;12:175.

Potter DR, Baimukanova G, Keating SM, Deng X, Chu JA, Gibb SL, et al. Fresh frozen plasma and spray-dried plasma mitigate pulmonary vascular permeability and inflammation in hemorrhagic shock. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S7–s17.

Torres LN, Sondeen JL, Dubick MA, Filho IT. Systemic and microvascular effects of resuscitation with blood products after severe hemorrhage in rats. J Trauma Acute Care Surg. 2014;77(5):716–23.

Broekhuizen LN, Lemkes BA, Mooij HL, Meuwese MC, Verberne H, Holleman F, et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia. 2010;53(12):2646–55.

Flameng W, Borgers M, Van der Vusse GJ, Demeyere R, Vandermeersch E, Thone F, et al. Cardioprotective effects of lidoflazine in extensive aorta-coronary bypass grafting. J Thorac Cardiovasc Surg. 1983;85(5):758–68.

Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63(4):805–13.

Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248(3):447–58.

Pati S, Matijevic N, Doursout MF, Ko T, Cao Y, Deng X, et al. Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw. J Trauma. 2010;69 Suppl 1:S55–63.

Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E. The antioxidant properties of serum albumin. FEBS Lett. 2008;582(13):1783–7.

Jorgensen KA, Stoffersen E. On the inhibitory effect of albumin on platelet aggregation. Thromb Res. 1980;17(1–2):13–8.

Richieri GV, Anel A, Kleinfeld AM. Interactions of long-chain fatty acids and albumin: determination of free fatty acid levels using the fluorescent probe ADIFAB. Biochemistry. 1993;32(29):7574–80.

Pardridge WM, Mietus LJ. Transport of steroid hormones through the rat blood–brain barrier. Primary role of albumin-bound hormone. J Clin Invest. 1979;64(1):145–54.

Devaraj S, Yun JM, Adamson G, Galvez J, Jialal I. C-reactive protein impairs the endothelial glycocalyx resulting in endothelial dysfunction. Cardiovasc Res. 2009;84(3):479–84.

Deng X, Cao Y, Huby MP, Duan C, Baer L, Peng Z, et al. Adiponectin in fresh frozen plasma contributes to restoration of vascular barrier function after hemorrhagic shock. Shock. 2016;45(1):50–4.

Peng Z, Pati S, Potter D, Brown R, Holcomb JB, Grill R, et al. Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan 1. Shock. 2013;40(3):195–202.

Nelson A, Statkevicius S, Schött U, Johansson PI, Bentzer P. Effects of fresh frozen plasma, Ringer’s acetate and albumin on plasma volume and on circulating glycocalyx components following haemorrhagic shock in rats. Intensive Care Med Exp. 2016;4:6.

Straat M, Muller MC, Meijers JC, Arbous MS, Spoelstra-de Man AM, Beurskens CJ, et al. Effect of transfusion of fresh frozen plasma on parameters of endothelial condition and inflammatory status in non-bleeding critically ill patients: a prospective substudy of a randomized trial. Crit Care. 2015;19:163.

Guo C, Tsigkou A, Lee MH. ADAMTS13 and 15 are not regulated by the full length and N-terminal domain forms of TIMP-1, −2, −3 and −4. Biomed Rep. 2016;4(1):5.