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• W3005158134 abstract "The endothelial glycocalyx is a vital regulator of vascular permeability. Damage to this delicate layer can result in increased protein and water transit. The clinical importance of albuminuria as a predictor of kidney disease progression and vascular disease has driven research in this area. This review outlines how research to date has attempted to measure the contribution of the endothelial glycocalyx to vessel wall permeability. We discuss the evidence for the role of the endothelial glycocalyx in regulating permeability in discrete areas of the vasculature and highlight the inherent limitations of the data that have been produced to date. In particular, this review emphasizes the difficulties in interpreting urinary albumin levels in early disease models. In addition, the research that supports the view that glycocalyx damage is a key pathologic step in a diverse array of clinical conditions, including diabetic complications, sepsis, preeclampsia, and atherosclerosis, is summarized. Finally, novel methods are discussed, including an ex vivo glomerular permeability assay that enhances the understanding of permeability changes in disease. The endothelial glycocalyx is a vital regulator of vascular permeability. Damage to this delicate layer can result in increased protein and water transit. The clinical importance of albuminuria as a predictor of kidney disease progression and vascular disease has driven research in this area. This review outlines how research to date has attempted to measure the contribution of the endothelial glycocalyx to vessel wall permeability. We discuss the evidence for the role of the endothelial glycocalyx in regulating permeability in discrete areas of the vasculature and highlight the inherent limitations of the data that have been produced to date. In particular, this review emphasizes the difficulties in interpreting urinary albumin levels in early disease models. In addition, the research that supports the view that glycocalyx damage is a key pathologic step in a diverse array of clinical conditions, including diabetic complications, sepsis, preeclampsia, and atherosclerosis, is summarized. Finally, novel methods are discussed, including an ex vivo glomerular permeability assay that enhances the understanding of permeability changes in disease. Water and solute exchange across the walls of the microcirculation are dynamic processes that are fundamental to tissue homeostasis. The net rates of exchange are regulated by alterations in systemic blood pressure (hydrostatic pressure), vessel density and size (surface area), flow rate, concentration gradients, and the intrinsic permeability properties of the vessel wall. The basic structure of the capillary wall is conserved throughout the body, consisting of an endothelial cell monolayer, basement membrane, and supporting cells. However, a high level of specialization occurs within discrete areas of the vasculature, optimizing the structure for the individual demands placed on it. The endothelial glycocalyx layer found on the luminal surface of all endothelial cells contributes to the permeability barrier formed by the vessel wall.1Betteridge K.B. Arkill K.P. Neal C.R. Harper S.J. Foster R.R. Satchell S.C. Bates D.O. Salmon A.H.J. Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function.J Physiol. 2017; 595: 5015-5035Crossref PubMed Scopus (73) Google Scholar,2Butler M.J. Ramnath R. Kadoya H. Desposito D. Riquier-Brison A. Ferguson J.K. Onions K.L. Ogier A.S. ElHegni H. Coward R.J. Welsh G.I. Foster R.R. Peti-Peterdi J. Satchell S.C. Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.Kidney Int. 2019; 95: 94-107Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Glycocalyx literally translates from the Greek for sugar coat (glykys means sweet and kalyx means husk). This adherent structure includes proteoglycans, glycoproteins, and glycolipids (Figure 1).1Betteridge K.B. Arkill K.P. Neal C.R. Harper S.J. Foster R.R. Satchell S.C. Bates D.O. Salmon A.H.J. Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function.J Physiol. 2017; 595: 5015-5035Crossref PubMed Scopus (73) Google Scholar,3Dane M.J. van den Berg B.M. Lee D.H. Boels M.G. Tiemeier G.L. Avramut M.C. van Zonneveld A.J. van der Vlag J. Vink H. Rabelink T.J. A microscopic view on the renal endothelial glycocalyx.Am J Physiol Renal Physiol. 2015; 308: F956-F966Crossref PubMed Scopus (86) Google Scholar, 4Singh A. Satchell S.C. Neal C.R. McKenzie E.A. Tooke J.E. Mathieson P.W. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability.J Am Soc Nephrol. 2007; 18: 2885-2893Crossref PubMed Scopus (207) Google Scholar, 5Curry F.R. Microvascular solute and water transport.Microcirculation. 2005; 12: 17-31Crossref PubMed Scopus (76) Google Scholar Proteoglycans consist of core proteins (eg, syndecans and glypicans) with covalently bound glycosaminoglycan side chains [eg, heparan sulfate (HS) and chondroitin sulfate]. The glycocalyx is not uniform across its depth.6Curry F.E. Layer upon layer: the functional consequences of disrupting the glycocalyx-endothelial barrier in vivo and in vitro.Cardiovasc Res. 2017; 113: 559-561Crossref PubMed Scopus (19) Google Scholar The 2-layer fiber matrix model suggests a dense 200- to 300-nm meshlike inner layer rich in proteoglycans covalently bound to the endothelial cell membrane and adherent glycosaminoglycans, including long chains of hyaluronan (HA), and an outer, more porous, gellike layer up to 1-μm thick, including adsorbed plasma proteins.6Curry F.E. Layer upon layer: the functional consequences of disrupting the glycocalyx-endothelial barrier in vivo and in vitro.Cardiovasc Res. 2017; 113: 559-561Crossref PubMed Scopus (19) Google Scholar,7Curry F.E. Michel C.C. The endothelial glycocalyx: barrier functions versus red cell hemodynamics: a model of steady state ultrafiltration through a bi-layer formed by a porous outer layer and more selective membrane-associated inner layer.Biorheology. 2019; 56: 113-130Crossref PubMed Scopus (9) Google Scholar This review discusses the evidence for the importance of the endothelial glycocalyx as a regulator of endothelial and vascular permeability, while noting the inherent difficulties in studying it. The human diseases in which glycocalyx damage and associated permeability alterations appear to be key pathogenic steps are also reviewed. Endothelial cells in vitro produce a surface glycocalyx that provides an accessible model to study glycocalyx functions, including shear stress sensing2Butler M.J. Ramnath R. Kadoya H. Desposito D. Riquier-Brison A. Ferguson J.K. Onions K.L. Ogier A.S. ElHegni H. Coward R.J. Welsh G.I. Foster R.R. Peti-Peterdi J. Satchell S.C. Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.Kidney Int. 2019; 95: 94-107Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar and permeability regulation.4Singh A. Satchell S.C. Neal C.R. McKenzie E.A. Tooke J.E. Mathieson P.W. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability.J Am Soc Nephrol. 2007; 18: 2885-2893Crossref PubMed Scopus (207) Google Scholar However, it is much thinner than the glycocalyx seen in vivo, limiting the applicability of in vitro research.4Singh A. Satchell S.C. Neal C.R. McKenzie E.A. Tooke J.E. Mathieson P.W. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability.J Am Soc Nephrol. 2007; 18: 2885-2893Crossref PubMed Scopus (207) Google Scholar,8Potter D.R. Damiano E.R. The hydrodynamically relevant endothelial cell glycocalyx observed in vivo is absent in vitro.Circ Res. 2008; 102: 770-776Crossref PubMed Scopus (143) Google Scholar,9Chappell D. Jacob M. Paul O. Rehm M. Welsch U. Stoeckelhuber M. Conzen P. Becker B.F. The glycocalyx of the human umbilical vein endothelial cell: an impressive structure ex vivo but not in culture.Circ Res. 2009; 104: 1313-1317Crossref PubMed Scopus (160) Google Scholar As a result, most studies on the permeability of the glycocalyx have been conducted in vivo. Much research to date has focused on the glomerular endothelial glycocalyx, which may be driven by the physiologic importance of permeability in glomerular function and the clinical importance of albuminuria. Furthermore, urinary albumin creatinine ratios (uACRs) can be easily quantified to provide a measure of albumin permeability across the glomerular filtration barrier (GFB) (Figure 1). Early models of the GFB overestimated the contribution of the slit diaphragm to the restriction of albumin filtration.10Edwards A. Daniels B.S. Deen W.M. Ultrastructural model for size selectivity in glomerular filtration.Am J Physiol. 1999; 276: F892-F902PubMed Google Scholar Recent models of the GFB, however, suggest that the glycocalyx represents a significant protein barrier.11Punyaratabandhu N. Kongoup P. Dechadilok P. Katavetin P. Triampo W. Transport of spherical particles through fibrous media and a row of parallel cylinders: applications to glomerular filtration.J Biomech Eng. 2017; 139: 121005Crossref Scopus (5) Google Scholar This finding concurs with accumulating experimental evidence,12Satchell S. The role of the glomerular endothelium in albumin handling.Nat Rev Nephrol. 2013; 9: 717-725Crossref PubMed Scopus (90) Google Scholar indicating that the remaining components of the GFB, including the endothelial glycocalyx, provide the major barrier to protein permeability (Figure 1).4Singh A. Satchell S.C. Neal C.R. McKenzie E.A. Tooke J.E. Mathieson P.W. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability.J Am Soc Nephrol. 2007; 18: 2885-2893Crossref PubMed Scopus (207) Google Scholar,13Weinbaum S. Tarbell J.M. Damiano E.R. The structure and function of the endothelial glycocalyx layer.Annu Rev Biomed Eng. 2007; 9: 121-167Crossref PubMed Scopus (823) Google Scholar, 14Salmon A.H. Satchell S.C. Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability.J Pathol. 2012; 226: 562-574Crossref PubMed Scopus (206) Google Scholar, 15Oltean S. Qiu Y. Ferguson J.K. Stevens M. Neal C. Russell A. Kaura A. Arkill K.P. Harris K. Symonds C. Lacey K. Wijeyaratne L. Gammons M. Wylie E. Hulse R.P. Alsop C. Cope G. Damodaran G. Betteridge K.B. Ramnath R. Satchell S.C. Foster R.R. Ballmer-Hofer K. Donaldson L.F. Barratt J. Baelde H.J. Harper S.J. Bates D.O. Salmon A.H. Vascular endothelial growth factor-A165b is protective and restores endothelial glycocalyx in diabetic nephropathy.J Am Soc Nephrol. 2015; 26: 1889-1904Crossref PubMed Scopus (101) Google Scholar These estimates, combined with the increased understanding of cellular crosstalk within the GFB, should make us question assumptions about the pathogenesis of albuminuria in multiple historical models.16Eremina V. Jefferson J.A. Kowalewska J. Hochster H. Haas M. Weisstuch J. Richardson C. Kopp J.B. Kabir M.G. Backx P.H. Gerber H.P. Ferrara N. Barisoni L. Alpers C.E. Quaggin S.E. VEGF inhibition and renal thrombotic microangiopathy.N Engl J Med. 2008; 358: 1129-1136Crossref PubMed Scopus (1165) Google Scholar,17Dimke H. Maezawa Y. Quaggin S.E. Crosstalk in glomerular injury and repair.Curr Opin Nephrol Hypertens. 2015; 24: 231-238PubMed Google Scholar Albuminuria is the net result of albumin passage across the GFB (influenced by permeability) and albumin reabsorption and metabolism within the renal tubules. However, despite the widespread use of uACR, there is increasing evidence in rodent models that uACR is not a sensitive test for changes in GFB permeability and hence not an ideal index of glycocalyx integrity. Using in vivo multiphoton microscopy in mice (Figure 2) (image provided by M.J.B.), we found that glomerular albumin leakage can be significantly increased before detectable levels of albumin appear in the urine.2Butler M.J. Ramnath R. Kadoya H. Desposito D. Riquier-Brison A. Ferguson J.K. Onions K.L. Ogier A.S. ElHegni H. Coward R.J. Welsh G.I. Foster R.R. Peti-Peterdi J. Satchell S.C. Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.Kidney Int. 2019; 95: 94-107Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Other groups have reported similar data, demonstrating increased glomerular albumin leakage but no significant change in uACR.18Dane M.J. van den Berg B.M. Avramut M.C. Faas F.G. van der Vlag J. Rops A.L. Ravelli R.B. Koster B.J. van Zonneveld A.J. Vink H. Rabelink T.J. Glomerular endothelial surface layer acts as a barrier against albumin filtration.Am J Pathol. 2013; 182: 1532-1540Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Evidence suggests that that this discrepancy is explained by tubular reabsorption of filtered albumin, resulting in a threshold effect whereby increased glomerular albumin permeability will not result in uACR increases until mechanisms of uptake and metabolism are overwhelmed.19Lazzara M.J. Deen W.M. Model of albumin reabsorption in the proximal tubule.Am J Physiol Renal Physiol. 2007; 292: F430-F439Crossref PubMed Scopus (60) Google Scholar The role of tubular albumin uptake in humans is debated, but diseases resulting in tubular dysfunction, such as Fanconi syndrome and Dent disease result in significant albuminuria.20Norden A.G. Scheinman S.J. Deschodt-Lanckman M.M. Lapsley M. Nortier J.L. Thakker R.V. Unwin R.J. Wrong O. Tubular proteinuria defined by a study of Dent's (CLCN5 mutation) and other tubular diseases.Kidney Int. 2000; 57: 240-249Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Historical studies in patients with diabetes using lysine to inhibit tubular albumin reabsorption similarly indicate that tubular albumin uptake may influence uACR results.21Gambaro G. Baggio B. Cicerello E. Mastrosimone S. Marzaro G. Borsatti A. Crepaldi G. Abnormal erythrocyte charge in diabetes mellitus: link with microalbuminuria.Diabetes. 1988; 37: 745-748Crossref PubMed Scopus (31) Google Scholar In summary, the clinical importance of albuminuria is now well established, but the absence of albuminuria in early rodent models of disease does not exclude increased albumin passage across the GFB. Relatively little research has been conducted studying glycocalyx-dependent permeability changes in the systemic vasculature. In part, this lack of research is attributable to the complex methods needed to study glycocalyx-specific changes. Previous studies in mesenteric microvessels by intravital confocal microscopy have demonstrated that neuraminidase, which disrupts sialic acid residues and reduces glycocalyx depth, increases microvessel permeability.1Betteridge K.B. Arkill K.P. Neal C.R. Harper S.J. Foster R.R. Satchell S.C. Bates D.O. Salmon A.H.J. Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function.J Physiol. 2017; 595: 5015-5035Crossref PubMed Scopus (73) Google Scholar Work that compares the depth of the endothelial glycocalyx within the continuous capillaries of the systemic and pulmonary vasculature highlighted significant variability in glycocalyx depth.22Ando Y. Okada H. Takemura G. Suzuki K. Takada C. Tomita H. Zaikokuji R. Hotta Y. Miyazaki N. Yano H. Muraki I. Kuroda A. Fukuda H. Kawasaki Y. Okamoto H. Kawaguchi T. Watanabe T. Doi T. Yoshida T. Ushikoshi H. Yoshida S. Ogura S. Brain-specific ultrastructure of capillary endothelial glycocalyx and its possible contribution for blood brain barrier.Sci Rep. 2018; 8: 17523Crossref PubMed Scopus (89) Google Scholar To date, little is known about whether the composition of the glycocalyx varies among these sites. It seems likely that the glycocalyx within discrete areas of the vasculature is specialized, adapting to perform the combination of tasks needed at each tissue site optimally. Variability in the glycocalyx structure means that pathologic insults may not affect all areas of the glycocalyx equally. Specialization is also seen in the endothelial monolayer itself. The double barrier concept was first introduced by Rehm et al23Rehm M. Zahler S. Lotsch M. Welsch U. Conzen P. Jacob M. Becker B.F. Endothelial glycocalyx as an additional barrier determining extravasation of 6% hydroxyethyl starch or 5% albumin solutions in the coronary vascular bed.Anesthesiology. 2004; 100: 1211-1223Crossref PubMed Scopus (210) Google Scholar and is illustrated in Figure 3. They found in guinea pig hearts that simultaneous disruption of both the cellular barrier (using ischemia or histamine) and glycocalyx damage (using heparinase) was needed to increase coronary vessel leakage.23Rehm M. Zahler S. Lotsch M. Welsch U. Conzen P. Jacob M. Becker B.F. Endothelial glycocalyx as an additional barrier determining extravasation of 6% hydroxyethyl starch or 5% albumin solutions in the coronary vascular bed.Anesthesiology. 2004; 100: 1211-1223Crossref PubMed Scopus (210) Google Scholar This work led to the hypothesis that glycocalyx damage overlying a tight cellular barrier will have minimal (direct) influence on monolayer or vessel wall permeability. In contrast, identical glycocalyx damage overlying a leaky cellular monolayer will result in rapid measurable increases in vessel permeability. When glycocalyx-dependent permeability changes within the systemic vasculature are studied, it is therefore important to consider how both glycocalyx structural adaptations and the underlying endothelial cell phenotype will influence detectable permeability changes. To measure the contribution of the endothelial glycocalyx to vessel permeability, comparisons have generally been made after a glycocalyx insult. Enzymatic removal or genetic knockdown of a specific glycocalyx component is commonly used for this purpose. However, the method used can significantly alter the results of such studies. Rapid removal of HS, using human heparanase or bacterial heparinase III, increased albumin passage across endothelial monolayers.4Singh A. Satchell S.C. Neal C.R. McKenzie E.A. Tooke J.E. Mathieson P.W. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability.J Am Soc Nephrol. 2007; 18: 2885-2893Crossref PubMed Scopus (207) Google Scholar However, knockout of the HS proteoglycan syndecan 1 did not result in albuminuria in mice.24Rops A.L. Gotte M. Baselmans M.H. van den Hoven M.J. Steenbergen E.J. Lensen J.F. Wijnhoven T.J. Cevikbas F. van den Heuvel L.P. van Kuppevelt T.H. Berden J.H. van der Vlag J. Syndecan-1 deficiency aggravates anti-glomerular basement membrane nephritis.Kidney Int. 2007; 72: 1204-1215Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar In addition, mice that lacked endothelial N-deacetylase and N-sulfotransferase, a key enzyme in modifying HS chains, did not become albuminuric.25Garsen M. Rops A.L. Rabelink T.J. Berden J.H. van der Vlag J. The role of heparanase and the endothelial glycocalyx in the development of proteinuria.Nephrol Dial Transplant. 2014; 29: 49-55Crossref PubMed Scopus (75) Google Scholar A similar pattern of results was seen in experiments that target HA. Hyaluronidase, an enzyme that degrades HA, has a plasma half-life of approximately 3 minutes before being taken up in the liver via a mannose-dependent mechanism.26Earnshaw J.S. Curtis C.G. Powell G.M. Dodgson K.S. Olavesen A.H. Gacesa P. The fate of intravenously administered highly purified bovine testicular hyaluronidase (Hyalosidase) in the rat.Biochem Pharmacol. 1985; 34: 2199-2203Crossref PubMed Scopus (11) Google Scholar The short plasma half-life and the relatively high molecular weight (55 to 61 kDa) of hyaluronidase result in a high level of glycocalyx-degrading activity with limited off-target effects. Several studies found that removing HA from the endothelial glycocalyx, using hyaluronidase, increased glomerular albumin transit 5.6-fold, a figure consistent with findings.27Landsverk S.A. Tsai A.G. Cabrales P. Intaglietta M. Impact of enzymatic degradation of the endothelial glycocalyx on vascular permeability in an awake hamster model.Crit Care Res Pract. 2012; 2012: 842545PubMed Google Scholar, 28Jeansson M. Haraldsson B. Glomerular size and charge selectivity in the mouse after exposure to glucosaminoglycan-degrading enzymes.J Am Soc Nephrol. 2003; 14: 1756-1765Crossref PubMed Scopus (115) Google Scholar, 29Onions K.L. Gamez M. Buckner N.R. Baker S.L. Betteridge K.B. Desideri S. Dallyn B.P. Ramnath R.D. Neal C.R. Farmer L.K. Mathieson P.W. Gnudi L. Alitalo K. Bates D.O. Salmon A.H.J. Welsh G.I. Satchell S.C. Foster R.R. VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy.Diabetes. 2019; 68: 172-187Crossref PubMed Scopus (33) Google Scholar Tamoxifen-induced endothelial-specific knockdown of HA synthase 2 (a membrane-bound HA synthesis enzyme) also resulted in significant albuminuria from 4 weeks after induction, which persisted to 12 weeks (experimental end point).30van den Berg B.M. Wang G. Boels M.G.S. Avramut M.C. Jansen E. Sol W. Lebrin F. Jan van Zonneveld A. de Koning E.J.P. Vink H. Grone H.J. Carmeliet P. van der Vlag J. Rabelink T.J. Glomerular function and structural integrity depend on hyaluronan synthesis by glomerular endothelium.J Am Soc Nephrol. 2019; 30: 1886-1897Crossref PubMed Scopus (37) Google Scholar In contrast, Dane et al18Dane M.J. van den Berg B.M. Avramut M.C. Faas F.G. van der Vlag J. Rops A.L. Ravelli R.B. Koster B.J. van Zonneveld A.J. Vink H. Rabelink T.J. Glomerular endothelial surface layer acts as a barrier against albumin filtration.Am J Pathol. 2013; 182: 1532-1540Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar found that 4 weeks of hyaluronidase infusion did not result in measurable albuminuria, although they found increased glomerular albumin leakage in 90% of glomeruli. Although this work, again, highlights the fact that albuminuria is a poor measure of low-level glomerular albumin leakage, it also suggests that the differences in time scale, as well as the precise component targeted, may influence glycocalyx permeability changes. Knockdown in genetic models may have resulted in compensatory adaptations (eg, up-regulation of other glycocalyx components). In contrast, the rapid enzymatic removal of glycocalyx components may prevent adaptations from occurring before functional assessments are made.25Garsen M. Rops A.L. Rabelink T.J. Berden J.H. van der Vlag J. The role of heparanase and the endothelial glycocalyx in the development of proteinuria.Nephrol Dial Transplant. 2014; 29: 49-55Crossref PubMed Scopus (75) Google Scholar,27Landsverk S.A. Tsai A.G. Cabrales P. Intaglietta M. Impact of enzymatic degradation of the endothelial glycocalyx on vascular permeability in an awake hamster model.Crit Care Res Pract. 2012; 2012: 842545PubMed Google Scholar, 28Jeansson M. Haraldsson B. Glomerular size and charge selectivity in the mouse after exposure to glucosaminoglycan-degrading enzymes.J Am Soc Nephrol. 2003; 14: 1756-1765Crossref PubMed Scopus (115) Google Scholar, 29Onions K.L. Gamez M. Buckner N.R. Baker S.L. Betteridge K.B. Desideri S. Dallyn B.P. Ramnath R.D. Neal C.R. Farmer L.K. Mathieson P.W. Gnudi L. Alitalo K. Bates D.O. Salmon A.H.J. Welsh G.I. Satchell S.C. Foster R.R. VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy.Diabetes. 2019; 68: 172-187Crossref PubMed Scopus (33) Google Scholar,31Gil N. Goldberg R. Neuman T. Garsen M. Zcharia E. Rubinstein A.M. van Kuppevelt T. Meirovitz A. Pisano C. Li J.P. van der Vlag J. Vlodavsky I. Elkin M. Heparanase is essential for the development of diabetic nephropathy in mice.Diabetes. 2012; 61: 208-216Crossref PubMed Scopus (144) Google Scholar In addition, the rapid removal of a single structural component of the glycocalyx may leave the structure as a whole vulnerable to further nonspecific destruction by the shear forces applied by the circulation. Another contrast between enzymatic removal and genetic knockdown of a glycocalyx component is the generation of circulating glycocalyx fragments. The enzymatic release of fragments is also nonspecific. Heparanase increased syndecan 1 and 4 loss from the glycocalyx structure, possibly by exposing cleavage sites for the actions of other circulating enzymes.32Jung O. Trapp-Stamborski V. Purushothaman A. Jin H. Wang H. Sanderson R.D. Rapraeger A.C. Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins.Oncogenesis. 2016; 5: e202Crossref PubMed Google Scholar The influence of active signaling fragments released after glycocalyx enzymatic degradation on vessel permeability has not been directly investigated, but they represent a potentially important pharmacologic target.33Kim E.Y. Roshanravan H. Dryer S.E. Syndecan-4 ectodomain evokes mobilization of podocyte TRPC6 channels and their associated pathways: an essential role for integrin signaling.Biochim Biophys Acta. 2015; 1853: 2610-2620Crossref PubMed Scopus (23) Google Scholar,34Zhang X. Han X. Xia K. Xu Y. Yang Y. Oshima K. Haeger S.M. Perez M.J. McMurtry S.A. Hippensteel J.A. Ford J.A. Herson P.S. Liu J. Schmidt E.P. Linhardt R.J. Circulating heparin oligosaccharides rapidly target the hippocampus in sepsis, potentially impacting cognitive functions.Proc Natl Acad Sci U S A. 2019; 116: 9208-9213Crossref PubMed Scopus (33) Google Scholar In summary, when the glycocalyx is studied, careful consideration needs to be given to the chosen method and tissue. Although the glomerular endothelial glycocalyx lends itself to studying permeability, the uACR should be interpreted with caution. Measures of systemic permeability need to be considered in context. A double barrier can exist, and in the absence of specific manipulations, the relative contributions of the components are difficult to establish. With the development of more sensitive and specific methods to assess permeability, the role of individual glycocalyx components are expected to be better understood in the next decade.35Desideri S. Onions K.L. Qiu Y. Ramnath R.D. Butler M.J. Neal C.R. King M.L.R. Salmon A.E. Saleem M.A. Welsh G.I. Michel C.C. Satchell S.C. Salmon A.H.J. Foster R.R. A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli.Kidney Int. 2018; 93: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar There is evidence that the diabetic milieu affects the vasculature globally. Nieuwdorp et al36Nieuwdorp M. van Haeften T.W. Gouverneur M.C. Mooij H.L. van Lieshout M.H. Levi M. Meijers J.C. Holleman F. Hoekstra J.B. Vink H. Kastelein J.J. Stroes E.S. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo.Diabetes. 2006; 55: 480-486Crossref PubMed Scopus (403) Google Scholar measured the total glycocalyx volume by comparing the volume of distribution of erythrocytes and dextran 40 in healthy volunteers. They found that 6 hours of hyperglycemia reduced the glycocalyx volume to 50% of the baseline value. More recently, an intervention trial found that intensification of glycemic control in poorly controlled type 2 diabetic patients during 12 months (glycated hemoglobin reduction from 74 to 54 mol/mol) was associated with a significant increase in glycocalyx depth compared with baseline vaulues.37Lambadiari V. Pavlidis G. Kousathana F. Maratou E. Georgiou D. Andreadou I. Kountouri A. Varoudi M. Balampanis K. Parissis J. Triantafyllidi H. Katogiannis K. Birba D. Lekakis J. Dimitriadis G. Ikonomidis I. Effects of different antidiabetic medications on endothelial glycocalyx, myocardial function, and vascular function in type 2 diabetic patients: one year follow-up study.J Clin Med. 2019; 8Crossref PubMed Scopus (20) Google Scholar Glycocalyx depth in this study was measured using side-stream dark field imaging to assess the perfused boundary region depth (a measure inversely proportional to glycocalyx thickness) on sublingual vessels, which suggests that systemic glycocalyx damage in early diabetes is at least partially reversible.37Lambadiari V. Pavlidis G. Kousathana F. Maratou E. Georgiou D. Andreadou I. Kountouri A. Varoudi M. Balampanis K. Parissis J. Triantafyllidi H. Katogiannis K. Birba D. Lekakis J. Dimitriadis G. Ikonomidis I. Effects of different antidiabetic medications on endothelial glycocalyx, myocardial function, and vascular function in type 2 diabetic patients: one year follow-up study.J Clin Med. 2019; 8Crossref PubMed Scopus (20) Google Scholar Changes to the endothelial glycocalyx occur early in the disease course, suggesting that they could represent a valuable direct therapeutic target.35Desideri S. Onions K.L. Qiu Y. Ramnath R.D. Butler M.J. Neal C.R. King M.L.R. Salmon A.E. Saleem M.A. Welsh G.I. Michel C.C. Satchell S.C. Salmon A.H.J. Foster R.R. A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli.Kidney Int. 2018; 93: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Electron microscopy on glomerular capillaries showed that the percentage surface covered by the glycocalyx is one of the earliest detectable vascular changes in diabetes.35Desideri S. Onions K.L. Qiu Y. Ramnath R.D. Butler M.J. Neal C.R. King M.L.R. Salmon A.E. Saleem M.A. Welsh G.I. Michel C.C. Satchell S.C. Salmon A.H.J. Foster R.R. A novel assay provides sensitive measurement of physiologically relevant ch" @default.
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• W3005158134 date "2020-04-01" @default.
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• W3005158134 title "The Pathological Relevance of Increased Endothelial Glycocalyx Permeability" @default.
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