Comprehensive Physiology Wiley Online Library

Endothelial Glycocalyx

Full Article on Wiley Online Library



Abstract

The glycocalyx is a polysaccharide structure that protrudes from the body of a cell. It is primarily conformed of glycoproteins and proteoglycans, which provide communication, electrostatic charge, ionic buffering, permeability, and mechanosensation‐mechanotransduction capabilities to cells. In blood vessels, the endothelial glycocalyx that projects into the vascular lumen separates the vascular wall from the circulating blood. Such a physical location allows a number of its components, including sialic acid, glypican‐1, heparan sulfate, and hyaluronan, to participate in the mechanosensation‐mechanotransduction of blood flow‐dependent shear stress, which results in the synthesis of nitric oxide and flow‐mediated vasodilation. The endothelial glycocalyx also participates in the regulation of vascular permeability and the modulation of inflammatory responses, including the processes of leukocyte rolling and extravasation. Its structural architecture and negative charge work to prevent macromolecules greater than approximately 70 kDa and cationic molecules from binding and flowing out of the vasculature. This also prevents the extravasation of pathogens such as bacteria and virus, as well as that of tumor cells. Due to its constant exposure to shear and circulating enzymes such as neuraminidase, heparanase, hyaluronidase, and matrix metalloproteinases, the endothelial glycocalyx is in a continuous process of degradation and renovation. A balance favoring degradation is associated with a variety of pathologies including atherosclerosis, hypertension, vascular aging, metastatic cancer, and diabetic vasculopathies. Consequently, ongoing research efforts are focused on deciphering the mechanisms that promote glycocalyx degradation or limit its syntheses, as well as on therapeutic approaches to improve glycocalyx integrity with the goal of reducing vascular disease. © 2022 American Physiological Society. Compr Physiol 12: 1–31, 2022.

Figure 1. Figure 1. Schematic illustration of the structural components of a small artery. The vascular wall consists of three distinct layers: the tunica externa (adventitia), the tunica media and the tunica intima. The adventitia is composed of collagen‐rich connective tissue containing fibroblasts and perivascular nerves. The tunica media contains mainly vascular smooth muscle cells and extracellular matrix (ECM) components including elastic laminas between smooth muscle layers as well as an internal elastic lamina that separates the tunica media and from the intima. The tunica intima contains a basement membrane and a monolayer of endothelial cells (endothelium) that synthesizes and anchors all components of the endothelial glycocalyx. Modified, with permission, from Martinez‐Lemus LA, 2012 182.
Figure 2. Figure 2. Schematic representation of the endothelial glycocalyx components. The endothelial glycocalyx is prominently present on the apical surface of the vascular endothelium. It has a brush‐like structure conformed of glycoproteins (e.g., CD44), some of which have attached glycosaminoglycan chains (e.g., heparan sulfate) that together form proteoglycan components (e.g., syndecan‐1). The glycocalyx components can be directly anchored to the cell membrane via transmembrane domains or via covalent links to molecules that associate with the endothelial plasmalemma. These anchoring associations include those with caveolin (Cav), protein kinase C (PKC), and other plasma membrane and intracellular molecules. They allow the glycocalyx to participate in the mechanotransduction of physical forces and the subsequent activation of intracellular pathways. Such pathways include the formation of calcium‐calmodulin (Ca‐Cam) complexes, the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS), the modulation of cytoskeletal structures, and the formation of endothelial focal adhesions. Overall the characteristics of the vascular endothelium are modulated by shedding and adsorption processes that change the abundance of each glycocalyx component present on the cell surface.
Figure 3. Figure 3. Schematic representation of the endothelial glycocalyx exposed to blood flow‐generated shear stress and the signaling cascade that results in shear stress‐generated nitric oxide (NO). The endothelial glycocalyx is exposed to laminar, oscillatory or disturbed blood flow patterns that deform, stimulate or shed glycocalyx components resulting in diverse outcomes, including the activation of endothelial NO synthase (eNOS), the production of NO and the subsequent induction of vasodilation.
Figure 4. Figure 4. Illustration of the forces that drive vascular permeability and their relationship with the endothelial glycocalyx. Under nonpathological conditions, the intact endothelial glycocalyx contributes significantly to the vascular permeability process as a physical and electrostatic barrier. Although the filtering of molecules is predominantly a function of cell‐cell adherens junctions and paracellular tight junctions, the negatively charged bush‐like structure of the glycocalyx, prevents the extravasation of macromolecules greater than approximately 70 kDa, as well as that of cationic molecules.
Figure 5. Figure 5. Two of the major sialic acid residues present in the endothelial glycocalyx are N‐acetylneuraminic acid and N‐glycolylneuraminic acid, which vary on their linkage to sugar moieties present in glycoprotein members of the glycocalyx.
Figure 6. Figure 6. The endothelial glycocalyx is negatively charged. This allows for the formation of a diffuse electrostatic barrier that separates the endothelium from other negatively charged blood components, such as red blood cells.
Figure 7. Figure 7. Schematic representation of the perfused boundary region (PBR) that allows for assessment of in vivo endothelial glycocalyx thickness. Flowing red blood cells (RBC) form a column as they travel within the vascular lumen. Blood velocity and the electrostatic charges of the endothelial glycocalyx as well as those of RBCs form a PBR, where only a few RBCs occasionally penetrate. The size of the median RBC column width subtracted from the vascular luminal diameter represents a measure of the PBR and the thickness of the endothelial glycocalyx. Modified, with permission, from Dane MJ, et al., 2015 56.
Figure 8. Figure 8. Schematic representation of the mechanisms that promote endothelial glycocalyx degradation. The endothelial glycocalyx undergoes a constant process of synthesis or adsorption and degradation or shedding. Degradation occurs in response to glycosaminoglycans (GAG) oxidation by reactive oxygen species (ROS) such as nitric oxide (NO), superoxide (O2), and H2O2, as well as by reactive nitrogen species (RNS) such as peroxynitrite (ONOO), N2O or N2O3. These reactive molecules are produced by multiple cellular components including mitochondria, endothelial NO synthase (eNOS), xanthine oxidase, and the NADPH oxidases (NOXes). Glycocalyx degradation also occurs by proteolysis or shedding mediated by enzymes such as the matrix metalloprotienases (MMPs) and the a disintegrin and metalloproteinases (ADAMs), amongst others. Glycocalyx degradation in turn increases vascular permeability and allows for exposure of proinflammatory receptors (e.g., P‐Selectin, ICAM, PE‐CAM, V‐CAM) that promote leukocyte rolling and adhesion to the vascular endothelium.
Figure 9. Figure 9. Homeostasis of the endothelial glycocalyx relies on an appropriate balance between glycocalyx degradation or shedding and biosynthesis or adsorption. However, numerous conditions tilt the balance toward glycocalyx degradation. Such conditions include disturbed blood flow patterns, hypertension, aging and diabetes. Exacerbated glycocalyx degradation exposes the vasculature to infiltration and adhesion of pathogens and pro‐inflammatory molecules, thus leading to vascular inflammation, atherosclerosis, and endothelial dysfunction. (A) schematic depiction of a healthy endothelial glycocalyx (left panel) and one in which disturbed blood flow, hypertension, aging or diabetes has favored its degradation. (B) Confocal microscope generated images of an isolated small artery showing the endothelial glycocalyx [stained with wheat germ agglutinin (WGA), green] and vascular cell nuclei [stained with 4′,6‐diamidino‐2‐phenylindole (DAPI), blue] before (left) and after (right) enzymatic degradation of the glycocalyx.
Figure 10. Figure 10. The endothelial glycocalyx is very fragile and difficult to measure. Today two commonly used techniques that provide ex vivo direct measurements of the in situ endothelial glycocalyx characteristics include atomic force microscopy (AFM) and transmitted electron microscopy (TEM). (A) AFM allows for the measurement of glycocalyx length and stiffness as assessed by the force curves generated when an AFM cantilever approaches and deforms the glycocalyx structures of en face isolated vascular preparations or cultured endothelial cells. (B) TEM allows for visualization of endothelial glycocalyx structures at the highest resolution currently available in microscopy, albeit, requiring complex sample preparation (Bar = 200 nm).


Figure 1. Schematic illustration of the structural components of a small artery. The vascular wall consists of three distinct layers: the tunica externa (adventitia), the tunica media and the tunica intima. The adventitia is composed of collagen‐rich connective tissue containing fibroblasts and perivascular nerves. The tunica media contains mainly vascular smooth muscle cells and extracellular matrix (ECM) components including elastic laminas between smooth muscle layers as well as an internal elastic lamina that separates the tunica media and from the intima. The tunica intima contains a basement membrane and a monolayer of endothelial cells (endothelium) that synthesizes and anchors all components of the endothelial glycocalyx. Modified, with permission, from Martinez‐Lemus LA, 2012 182.


Figure 2. Schematic representation of the endothelial glycocalyx components. The endothelial glycocalyx is prominently present on the apical surface of the vascular endothelium. It has a brush‐like structure conformed of glycoproteins (e.g., CD44), some of which have attached glycosaminoglycan chains (e.g., heparan sulfate) that together form proteoglycan components (e.g., syndecan‐1). The glycocalyx components can be directly anchored to the cell membrane via transmembrane domains or via covalent links to molecules that associate with the endothelial plasmalemma. These anchoring associations include those with caveolin (Cav), protein kinase C (PKC), and other plasma membrane and intracellular molecules. They allow the glycocalyx to participate in the mechanotransduction of physical forces and the subsequent activation of intracellular pathways. Such pathways include the formation of calcium‐calmodulin (Ca‐Cam) complexes, the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS), the modulation of cytoskeletal structures, and the formation of endothelial focal adhesions. Overall the characteristics of the vascular endothelium are modulated by shedding and adsorption processes that change the abundance of each glycocalyx component present on the cell surface.


Figure 3. Schematic representation of the endothelial glycocalyx exposed to blood flow‐generated shear stress and the signaling cascade that results in shear stress‐generated nitric oxide (NO). The endothelial glycocalyx is exposed to laminar, oscillatory or disturbed blood flow patterns that deform, stimulate or shed glycocalyx components resulting in diverse outcomes, including the activation of endothelial NO synthase (eNOS), the production of NO and the subsequent induction of vasodilation.


Figure 4. Illustration of the forces that drive vascular permeability and their relationship with the endothelial glycocalyx. Under nonpathological conditions, the intact endothelial glycocalyx contributes significantly to the vascular permeability process as a physical and electrostatic barrier. Although the filtering of molecules is predominantly a function of cell‐cell adherens junctions and paracellular tight junctions, the negatively charged bush‐like structure of the glycocalyx, prevents the extravasation of macromolecules greater than approximately 70 kDa, as well as that of cationic molecules.


Figure 5. Two of the major sialic acid residues present in the endothelial glycocalyx are N‐acetylneuraminic acid and N‐glycolylneuraminic acid, which vary on their linkage to sugar moieties present in glycoprotein members of the glycocalyx.


Figure 6. The endothelial glycocalyx is negatively charged. This allows for the formation of a diffuse electrostatic barrier that separates the endothelium from other negatively charged blood components, such as red blood cells.


Figure 7. Schematic representation of the perfused boundary region (PBR) that allows for assessment of in vivo endothelial glycocalyx thickness. Flowing red blood cells (RBC) form a column as they travel within the vascular lumen. Blood velocity and the electrostatic charges of the endothelial glycocalyx as well as those of RBCs form a PBR, where only a few RBCs occasionally penetrate. The size of the median RBC column width subtracted from the vascular luminal diameter represents a measure of the PBR and the thickness of the endothelial glycocalyx. Modified, with permission, from Dane MJ, et al., 2015 56.


Figure 8. Schematic representation of the mechanisms that promote endothelial glycocalyx degradation. The endothelial glycocalyx undergoes a constant process of synthesis or adsorption and degradation or shedding. Degradation occurs in response to glycosaminoglycans (GAG) oxidation by reactive oxygen species (ROS) such as nitric oxide (NO), superoxide (O2), and H2O2, as well as by reactive nitrogen species (RNS) such as peroxynitrite (ONOO), N2O or N2O3. These reactive molecules are produced by multiple cellular components including mitochondria, endothelial NO synthase (eNOS), xanthine oxidase, and the NADPH oxidases (NOXes). Glycocalyx degradation also occurs by proteolysis or shedding mediated by enzymes such as the matrix metalloprotienases (MMPs) and the a disintegrin and metalloproteinases (ADAMs), amongst others. Glycocalyx degradation in turn increases vascular permeability and allows for exposure of proinflammatory receptors (e.g., P‐Selectin, ICAM, PE‐CAM, V‐CAM) that promote leukocyte rolling and adhesion to the vascular endothelium.


Figure 9. Homeostasis of the endothelial glycocalyx relies on an appropriate balance between glycocalyx degradation or shedding and biosynthesis or adsorption. However, numerous conditions tilt the balance toward glycocalyx degradation. Such conditions include disturbed blood flow patterns, hypertension, aging and diabetes. Exacerbated glycocalyx degradation exposes the vasculature to infiltration and adhesion of pathogens and pro‐inflammatory molecules, thus leading to vascular inflammation, atherosclerosis, and endothelial dysfunction. (A) schematic depiction of a healthy endothelial glycocalyx (left panel) and one in which disturbed blood flow, hypertension, aging or diabetes has favored its degradation. (B) Confocal microscope generated images of an isolated small artery showing the endothelial glycocalyx [stained with wheat germ agglutinin (WGA), green] and vascular cell nuclei [stained with 4′,6‐diamidino‐2‐phenylindole (DAPI), blue] before (left) and after (right) enzymatic degradation of the glycocalyx.


Figure 10. The endothelial glycocalyx is very fragile and difficult to measure. Today two commonly used techniques that provide ex vivo direct measurements of the in situ endothelial glycocalyx characteristics include atomic force microscopy (AFM) and transmitted electron microscopy (TEM). (A) AFM allows for the measurement of glycocalyx length and stiffness as assessed by the force curves generated when an AFM cantilever approaches and deforms the glycocalyx structures of en face isolated vascular preparations or cultured endothelial cells. (B) TEM allows for visualization of endothelial glycocalyx structures at the highest resolution currently available in microscopy, albeit, requiring complex sample preparation (Bar = 200 nm).
References
 1.Agren MS, Auf dem Keller U. Matrix metalloproteinases: How much can they do? Int J Mol Sci 21: 1‐9, 2020.
 2.Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100: 158‐173, 2007.
 3.Albarran‐Juarez J, Iring A, Wang S, Joseph S, Grimm M, Strilic B, Wettschureck N, Althoff TF, Offermanns S. Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation. J Exp Med 215: 2655‐2672, 2018.
 4.Ali MM, Mahmoud AM, Le Master E, Levitan I, Phillips SA. Role of matrix metalloproteinases and histone deacetylase in oxidative stress‐induced degradation of the endothelial glycocalyx. Am J Physiol Heart Circ Physiol 316: H647‐H663, 2019.
 5.Almenara CCP, Oliveira TF, Padilha AS. The role of antioxidants in the prevention of cadmium‐induced endothelial dysfunction. Curr Pharm Des 26: 3667‐3675, 2020.
 6.Alphonsus CS, Rodseth RN. The endothelial glycocalyx: A review of the vascular barrier. Anaesthesia 69: 777‐784, 2014.
 7.Ando J, Yamamoto K. Flow detection and calcium signalling in vascular endothelial cells. Cardiovasc Res 99: 260‐268, 2013.
 8.Arabyan N, Park D, Foutouhi S, Weis AM, Huang BC, Williams CC, Desai P, Shah J, Jeannotte R, Kong N, Lebrilla CB, Weimer BC. Salmonella degrades the host glycocalyx leading to altered infection and glycan remodeling. Sci Rep 6: 29525, 2016.
 9.Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C. Pericytes regulate the blood‐brain barrier. Nature 468: 557‐561, 2010.
 10.Badenes M, Amin A, Gonzalez‐Garcia I, Felix I, Burbridge E, Cavadas M, Ortega FJ, de Carvalho E, Faisca P, Carobbio S, Seixas E, Pedroso D, Neves‐Costa A, Moita LF, Fernandez‐Real JM, Vidal‐Puig A, Domingos A, Lopez M, Adrain C. Deletion of iRhom2 protects against diet‐induced obesity by increasing thermogenesis. Mol Metab 31: 67‐84, 2020.
 11.Bai A, Hu H, Yeung M, Chen J. Kruppel‐like factor 2 controls T cell trafficking by activating L‐selectin (CD62L) and sphingosine‐1‐phosphate receptor 1 transcription. J Immunol 178: 7632‐7639, 2007.
 12.Baker AB, Chatzizisis YS, Beigel R, Jonas M, Stone BV, Coskun AU, Maynard C, Rogers C, Koskinas KC, Feldman CL, Stone PH, Edelman ER. Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine. Atherosclerosis 213: 436‐442, 2010.
 13.Baker AB, Gibson WJ, Kolachalama VB, Golomb M, Indolfi L, Spruell C, Zcharia E, Vlodavsky I, Edelman ER. Heparanase regulates thrombosis in vascular injury and stent‐induced flow disturbance. J Am Coll Cardiol 59: 1551‐1560, 2012.
 14.Baratchi S, Khoshmanesh K, Woodman OL, Potocnik S, Peter K, McIntyre P. Molecular sensors of blood flow in endothelial cells. Trends Mol Med 23: 850‐868, 2017.
 15.Barenwaldt A, Laubli H. The sialoglycan‐Siglec glyco‐immune checkpoint—a target for improving innate and adaptive anti‐cancer immunity. Expert Opin Ther Targets 23: 839‐853, 2019.
 16.Barth D, Knoepp F, Fronius M. Enhanced shear force responsiveness of epithelial Na(+) channel's (ENaC) δ subunit following the insertion of N‐glycosylation motifs relies on the extracellular matrix. Int J Mol Sci 22: 1‐13, 2021.
 17.Bartke N, Hannun YA. Bioactive sphingolipids: Metabolism and function. J Lipid Res 50 Suppl: S91‐S96, 2009.
 18.Bartosch AMW, Mathews R, Tarbell JM. Endothelial glycocalyx‐mediated nitric oxide production in response to selective AFM pulling. Biophys J 113: 101‐108, 2017.
 19.Bates DO, Levick JR, Mortimer PS. Starling pressures in the human arm and their alteration in postmastectomy oedema. J Physiol 477: 355‐363, 1994.
 20.Beatty PR, Puerta‐Guardo H, Killingbeck SS, Glasner DR, Hopkins K, Harris E. Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci Transl Med 7: 304ra141, 2015.
 21.Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: Acute deficits, but great potential. Cardiovasc Res 87: 300‐310, 2010.
 22.Bendas G, Borsig L. Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012: 676731, 2012.
 23.Bennett HS. Morphological aspects of extracellular polysaccharides. J Histochem Cytochem 11: 14‐23, 1963.
 24.Betteridge KB, Arkill KP, Neal CR, Harper SJ, Foster RR, Satchell SC, Bates DO, Salmon AHJ. Sialic acids regulate microvessel permeability, revealed by novel in vivo studies of endothelial glycocalyx structure and function. J Physiol 595: 5015‐5035, 2017.
 25.Bills VL, Salmon AH, Harper SJ, Overton TG, Neal CR, Jeffery B, Soothill PW, Bates DO. Impaired vascular permeability regulation caused by the VEGF(1)(6)(5)b splice variant in pre‐eclampsia. BJOG 118: 1253‐1261, 2011.
 26.Black RA. Tumor necrosis factor‐alpha converting enzyme. Int J Biochem Cell Biol 34: 1‐5, 2002.
 27.Blaum BS, Hannan JP, Herbert AP, Kavanagh D, Uhrin D, Stehle T. Structural basis for sialic acid‐mediated self‐recognition by complement factor H. Nat Chem Biol 11: 77‐82, 2015.
 28.Bode C, Sensken SC, Peest U, Beutel G, Thol F, Levkau B, Li Z, Bittman R, Huang T, Tölle M, van der Giet M, Gräler MH. Erythrocytes serve as a reservoir for cellular and extracellular sphingosine 1‐phosphate. J Cell Biochem 109: 1232‐1243.
 29.Bovio F, Epistolio S, Mozzi A, Monti E, Fusi P, Forcella M, Frattini M. Role of NEU3 overexpression in the prediction of efficacy of EGFR‐targeted therapies in colon cancer cell lines. Int J Mol Sci 21: 1‐16, 2020.
 30.Brands J, Van Teeffelen JW, Van den Berg B, Vink H. Role for glycocalyx perturbation in atherosclerosis development and associated microvascular dysfunction. Futur Lipidol 2: 527‐534, 2007.
 31.Broekhuizen LN, Lemkes BA, Mooij HL, Meuwese MC, Verberne H, Holleman F, Schlingemann RO, Nieuwdorp M, Stroes ES, Vink H. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia 53: 2646‐2655, 2010.
 32.Brouns SLN, Provenzale I, van Geffen JP, van der Meijden PEJ, Heemskerk JWM. Localized endothelial‐based control of platelet aggregation and coagulation under flow: A proof‐of‐principle vessel‐on‐a‐chip study. J Thromb Haemost 18: 931‐941, 2020.
 33.Buffone A, Weaver VM. Don't sugarcoat it: How glycocalyx composition influences cancer progression. J Cell Biol 219: 1‐14, 2020.
 34.Bull C, Stoel MA, den Brok MH, Adema GJ. Sialic acids sweeten a tumor's life. Cancer Res 74: 3199‐3204, 2014.
 35.Butler MJ, Down CJ, Foster RR, Satchell SC. The pathological relevance of increased endothelial glycocalyx permeability. Am J Pathol 190: 742‐751, 2020.
 36.Campo GM, Avenoso A, Campo S, D'Ascola A, Traina P, Sama D, Calatroni A. NF‐kB and caspases are involved in the hyaluronan and chondroitin‐4‐sulphate‐exerted antioxidant effect in fibroblast cultures exposed to oxidative stress. J Appl Toxicol 28: 509‐517, 2008.
 37.Campo GM, D'Ascola A, Avenoso A, Campo S, Ferlazzo AM, Micali C, Zanghi L, Calatroni A. Glycosaminoglycans reduce oxidative damage induced by copper (Cu+2), iron (Fe+2) and hydrogen peroxide (H2O2) in human fibroblast cultures. Glycoconj J 20: 133‐141, 2004.
 38.Cancel LM, Ebong EE, Mensah S, Hirschberg C, Tarbell JM. Endothelial glycocalyx, apoptosis and inflammation in an atherosclerotic mouse model. Atherosclerosis 252: 136‐146, 2016.
 39.Cantalupo A, Gargiulo A, Dautaj E, Liu C, Zhang Y, Hla T, Di Lorenzo A. S1PR1 (sphingosine‐1‐phosphate receptor 1) signaling regulates blood flow and pressure. Hypertension 70: 426‐434, 2017.
 40.Carey DJ. Syndecans: Multifunctional cell‐surface co‐receptors. Biochem J 327 (Pt 1): 1‐16, 1997.
 41.Chajara A, Raoudi M, Delpech B, Leroy M, Basuyau JP, Levesque H. Increased hyaluronan and hyaluronidase production and hyaluronan degradation in injured aorta of insulin‐resistant rats. Arterioscler Thromb Vasc Biol 20: 1480‐1487, 2000.
 42.Chari SN, Nath N. Sialic acid content and sialidase activity of polymorphonuclear leucocytes in diabetes mellitus. Am J Med Sci 288: 18‐20, 1984.
 43.Chatterjee S, Fisher AB. Mechanotransduction in the endothelium: Role of membrane proteins and reactive oxygen species in sensing, transduction, and transmission of the signal with altered blood flow. Antioxid Redox Signal 20: 899‐913, 2014.
 44.Cheng F, Mani K, van den Born J, Ding K, Belting M, Fransson LA. Nitric oxide‐dependent processing of heparan sulfate in recycling S‐nitrosylated glypican‐1 takes place in caveolin‐1‐containing endosomes. J Biol Chem 277: 44431‐44439, 2002.
 45.Chistyakov DV, Astakhova AA, Azbukina NV, Goriainov SV, Chistyakov VV, Sergeeva MG. High and low molecular weight hyaluronic acid differentially influences oxylipins synthesis in course of neuroinflammation. Int J Mol Sci 20: 1‐14, 2019.
 46.Constantinescu AA, Vink H, Spaan JA. Elevated capillary tube hematocrit reflects degradation of endothelial cell glycocalyx by oxidized LDL. Am J Physiol Heart Circ Physiol 280: H1051‐H1057, 2001.
 47.Cornelius DC. Preeclampsia: From inflammation to immunoregulation. Clin Med Insights Blood Disord 11: 1179545X17752325, 2018.
 48.Cosgun ZC, Fels B, Kusche‐Vihrog K. Nanomechanics of the endothelial glycocalyx: From structure to function. Am J Pathol 190: 732‐741, 2020.
 49.Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol 7: 255‐266, 2007.
 50.Cutler SJ, Doecke JD, Ghazawi I, Yang J, Griffiths LR, Spring KJ, Ralph SJ, Mellick AS. Novel STAT binding elements mediate IL‐6 regulation of MMP‐1 and MMP‐3. Sci Rep 7: 8526, 2017.
 51.D'Addio M, Frey J, Otto VI. The manifold roles of sialic acid for the biological functions of endothelial glycoproteins. Glycobiology 30: 490‐499, 2020.
 52.D'Agostino A, Stellavato A, Corsuto L, Diana P, Filosa R, La Gatta A, De Rosa M, Schiraldi C. Is molecular size a discriminating factor in hyaluronan interaction with human cells? Carbohydr Polym 157: 21‐30, 2017.
 53.Dai G, Kaazempur‐Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia‐Cardena G, Gimbrone MA Jr. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis‐susceptible and ‐resistant regions of human vasculature. Proc Natl Acad Sci U S A 101: 14871‐14876, 2004.
 54.Dai G, Vaughn S, Zhang Y, Wang ET, Garcia‐Cardena G, Gimbrone MA Jr. Biomechanical forces in atherosclerosis‐resistant vascular regions regulate endothelial redox balance via phosphoinositol 3‐kinase/Akt‐dependent activation of Nrf2. Circ Res 101: 723‐733, 2007.
 55.Dall'Olio F, Malagolini N, Trinchera M, Chiricolo M. Sialosignaling: Sialyltransferases as engines of self‐fueling loops in cancer progression. Biochim Biophys Acta 1840: 2752‐2764, 2014.
 56.Dane MJ, van den Berg BM, Lee DH, Boels MG, Tiemeier GL, Avramut MC, van Zonneveld AJ, van der Vlag J, Vink H, Rabelink TJ. A microscopic view on the renal endothelial glycocalyx. Am J Physiol Renal Physiol 308: F956‐F966, 2015.
 57.Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 6: 16‐26, 2009.
 58.de Queiroz TM, Lakkappa N, Lazartigues E. ADAM17‐mediated shedding of inflammatory cytokines in hypertension. Front Pharmacol 11: 1154, 2020.
 59.DeGrendele HC, Estess P, Picker LJ, Siegelman MH. CD44 and its ligand hyaluronate mediate rolling under physiologic flow: A novel lymphocyte‐endothelial cell primary adhesion pathway. J Exp Med 183: 1119‐1130, 1996.
 60.Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE‐cadherin in the control of vascular permeability. J Cell Sci 121: 2115‐2122, 2008.
 61.Delgadillo LF, Marsh GA, Waugh RE. Endothelial glycocalyx layer properties and its ability to limit leukocyte adhesion. Biophys J 118: 1564‐1575, 2020.
 62.Dennis JW, Nabi IR, Demetriou M. Metabolism, cell surface organization, and disease. Cell 139: 1229‐1241, 2009.
 63.Ding Z, Wang X, Khaidakov M, Liu S, Dai Y, Mehta JL. Degradation of heparan sulfate proteoglycans enhances oxidized‐LDL‐mediated autophagy and apoptosis in human endothelial cells. Biochem Biophys Res Commun 426: 106‐111, 2012.
 64.Dogne S, Flamion B. Endothelial glycocalyx impairment in disease: Focus on hyaluronan shedding. Am J Pathol 190: 768‐780, 2020.
 65.Dogne S, Flamion B, Caron N. Endothelial glycocalyx as a shield against diabetic vascular complications: Involvement of hyaluronan and hyaluronidases. Arterioscler Thromb Vasc Biol 38: 1427‐1439, 2018.
 66.Dogne S, Rath G, Jouret F, Caron N, Dessy C, Flamion B. Hyaluronidase 1 deficiency preserves endothelial function and glycocalyx integrity in early streptozotocin‐induced diabetes. Diabetes 65: 2742‐2753, 2016.
 67.Dolmatova EV, Wang K, Mandavilli R, Griendling KK. The effects of sepsis on endothelium and clinical implications. Cardiovasc Res 117: 60‐73, 2020.
 68.Donati A, Damiani E, Domizi R, Romano R, Adrario E, Pelaia P, Ince C, Singer M. Alteration of the sublingual microvascular glycocalyx in critically ill patients. Microvasc Res 90: 86‐89, 2013.
 69.Dou H, Feher A, Davila AC, Romero MJ, Patel VS, Kamath VM, Gooz MB, Rudic RD, Lucas R, Fulton DJ, Weintraub NL, Bagi Z. Role of adipose tissue endothelial ADAM17 in age‐related coronary microvascular dysfunction. Arterioscler Thromb Vasc Biol 37: 1180‐1193, 2017.
 70.Dragovich MA, Chester D, Fu BM, Wu C, Xu Y, Goligorsky MS, Zhang XF. Mechanotransduction of the endothelial glycocalyx mediates nitric oxide production through activation of TRP channels. Am J Physiol Cell Physiol 311: C846‐C853, 2016.
 71.Drummond GR, Sobey CG. Endothelial NADPH oxidases: Which NOX to target in vascular disease? Trends Endocrinol Metab 25: 452‐463, 2014.
 72.Duran WN, Breslin JW, Sanchez FA. The NO cascade, eNOS location, and microvascular permeability. Cardiovasc Res 87: 254‐261, 2010.
 73.Ebong EE, Lopez‐Quintero SV, Rizzo V, Spray DC, Tarbell JM. Shear‐induced endothelial NOS activation and remodeling via heparan sulfate, glypican‐1, and syndecan‐1. Integr Biol 6: 338‐347, 2014.
 74.Ebong EE, Macaluso FP, Spray DC, Tarbell JM. Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler Thromb Vasc Biol 31: 1908‐1915, 2011.
 75.Ecobici M, Stoicescu C. arterial stiffness and hypertension—which comes first? Maedica (Bucur) 12: 184‐190, 2017.
 76.Engin A. Endothelial dysfunction in obesity. Adv Exp Med Biol 960: 345‐379, 2017.
 77.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 12: 175, 2013.
 78.Esko JD, Linhardt RJ. Proteins that bind sulfated glycosaminoglycans. In: Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler ME, editors. Essentials of Glycobiology. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2009.
 79.Eylar EH, Madoff MA, Brody OV, Oncley JL. The contribution of sialic acid to the surface charge of the erythrocyte. J Biol Chem 237: 1992‐2000, 1962.
 80.Fan D, Takawale A, Shen M, Samokhvalov V, Basu R, Patel V, Wang X, Fernandez‐Patron C, Seubert JM, Oudit GY, Kassiri Z. A disintegrin and metalloprotease‐17 regulates pressure overload‐induced myocardial hypertrophy and dysfunction through proteolytic processing of integrin beta1. Hypertension 68: 937‐948, 2016.
 81.Fan J, Sun Y, Xia Y, Tarbell JM, Fu BM. Endothelial surface glycocalyx (ESG) components and ultra‐structure revealed by stochastic optical reconstruction microscopy (STORM). Biorheology 56: 77‐88, 2019.
 82.Fancher IS, Le Master E, Ahn SJ, Adamos C, Lee JC, Berdyshev E, Dull RO, Phillips SA, Levitan I. Impairment of flow‐sensitive inwardly rectifying k(+) channels via disruption of glycocalyx mediates obesity‐induced endothelial dysfunction. Arterioscler Thromb Vasc Biol 40: e240‐e255, ATVBAHA120314935, 2020.
 83.Fels B, Kusche‐Vihrog K. It takes more than two to tango: Mechanosignaling of the endothelial surface. Pflugers Arch 472: 419‐433, 2020.
 84.Fels J, Jeggle P, Liashkovich I, Peters W, Oberleithner H. Nanomechanics of vascular endothelium. Cell Tissue Res 355: 727‐737, 2014.
 85.Filmus J, Capurro M, Rast J. Glypicans. Genome Biol 9: 224, 2008.
 86.Fingleton B. Matrix metalloproteinases as regulators of inflammatory processes. Biochim Biophys Acta Mol Cell Res 1864: 2036‐2042, 2017.
 87.Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM. Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res 93: e136‐e142, 2003.
 88.Foote CA, Castorena‐Gonzalez JA, Ramirez‐Perez FI, Jia G, Hill MA, Reyes‐Aldasoro CC, Sowers JR, Martinez‐Lemus LA. Arterial stiffening in western diet‐fed mice is associated with increased vascular elastin, transforming growth factor‐beta, and plasma neuraminidase. Front Physiol 7: 285, 2016.
 89.Fox TE, Bewley MC, Unrath KA, Pedersen MM, Anderson RE, Jung DY, Jefferson LS, Kim JK, Bronson SK, Flanagan JM. Circulating sphingolipid biomarkers in models of type 1 diabetes. J Lipid Res 52: 509‐517, 2011.
 90.Franchimont N, Lambert C, Huynen P, Ribbens C, Relic B, Chariot A, Bours V, Piette J, Merville MP, Malaise M. Interleukin‐6 receptor shedding is enhanced by interleukin‐1beta and tumor necrosis factor alpha and is partially mediated by tumor necrosis factor alpha‐converting enzyme in osteoblast‐like cells. Arthritis Rheum 52: 84‐93, 2005.
 91.Fransson LA, Belting M, Cheng F, Jonsson M, Mani K, Sandgren S. Novel aspects of glypican glycobiology. Cell Mol Life Sci 61: 1016‐1024, 2004.
 92.Fraser JR, Laurent TC, Laurent UB. Hyaluronan: Its nature, distribution, functions and turnover. J Intern Med 242: 27‐33, 1997.
 93.Fronek K, Zweifach BW. Microvascular pressure distribution in skeletal muscle and the effect of vasodilation. Am J Phys 228: 791‐796, 1975.
 94.Fukai T, Ushio‐Fukai M. Superoxide dismutases: Role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15: 1583‐1606, 2011.
 95.Gao L, Lipowsky HH. Composition of the endothelial glycocalyx and its relation to its thickness and diffusion of small solutes. Microvasc Res 80: 394‐401, 2010.
 96.George J, Struthers A. The role of urate and xanthine oxidase in vascular oxidative stress: Future directions. Ther Clin Risk Manag 5: 799‐803, 2009.
 97.Gerhold KA, Schwartz MA. Ion channels in endothelial responses to fluid shear stress. Physiology (Bethesda) 31: 359‐369, 2016.
 98.Ghosh A, Kuppusamy H, Pilarski LM. Aberrant splice variants of HAS1 (Hyaluronan Synthase 1) multimerize with and modulate normally spliced HAS1 protein: A potential mechanism promoting human cancer. J Biol Chem 284: 18840‐18850, 2009.
 99.Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 107: 1058‐1070, 2010.
 100.Glanz VY, Myasoedova VA, Grechko AV, Orekhov AN. Sialidase activity in human pathologies. Eur J Pharmacol 842: 345‐350, 2019.
 101.Goldberg R, Rubinstein AM, Gil N, Hermano E, Li JP, van der Vlag J, Atzmon R, Meirovitz A, Elkin M. Role of heparanase‐driven inflammatory cascade in pathogenesis of diabetic nephropathy. Diabetes 63: 4302‐4313, 2014.
 102.Goligorsky MS, Sun D. Glycocalyx in endotoxemia and sepsis. Am J Pathol 190: 791‐798, 2020.
 103.Golovanova NK, Gracheva EV, Il'inskaya OP, Tararak EM, Prokazova NV. Sialidase activity in normal and atherosclerotic human aortic intima. Biochemistry (Mosc) 67: 1230‐1234, 2002.
 104.Gooz M. ADAM‐17: The enzyme that does it all. Crit Rev Biochem Mol Biol 45: 146‐169, 2010.
 105.Gouverneur M, Berg B, Nieuwdorp M, Stroes E, Vink H. Vasculoprotective properties of the endothelial glycocalyx: Effects of fluid shear stress. J Intern Med 259: 393‐400, 2006.
 106.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 290: H458‐H452, 2006.
 107.Guillaumet‐Adkins A, Yanez Y, Peris‐Diaz MD, Calabria I, Palanca‐Ballester C, Sandoval J. Epigenetics and oxidative stress in aging. Oxidative Med Cell Longev 2017: 9175806, 2017.
 108.Guo J, Yang ZC, Liu Y. Attenuating pulmonary hypertension by protecting the integrity of glycocalyx in rats model of pulmonary artery hypertension. Inflammation 42: 1951‐1956, 2019.
 109.Hamidi H, Ivaska J. Every step of the way: Integrins in cancer progression and metastasis. Nat Rev Cancer 18: 533‐548, 2018.
 110.Hascall V, Esko JD. Hyaluronan. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Darvill AG, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH, editors. Essentials of Glycobiology. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2015, p. 197‐206.
 111.Hempel C, Pasini EM, Kurtzhals JAL. Endothelial glycocalyx: Shedding light on malaria pathogenesis. Trends Mol Med 22: 453‐457, 2016.
 112.Henry CB, Duling BR. TNF‐alpha increases entry of macromolecules into luminal endothelial cell glycocalyx. Am J Physiol Heart Circ Physiol 279: H2815‐H2823, 2000.
 113.Hill MA, Nourian Z, Ho IL, Clifford PS, Martinez‐Lemus L, Meininger GA. Small artery elastin distribution and architecture—focus on three dimensional organization. Microcirculation 23: 614‐620, 2016.
 114.Hodge‐Dufour J, Noble PW, Horton MR, Bao C, Wysoka M, Burdick MD, Strieter RM, Trinchieri G, Pure E. Induction of IL‐12 and chemokines by hyaluronan requires adhesion‐dependent priming of resident but not elicited macrophages. J Immunol 159: 2492‐2500, 1997.
 115.Hooke R. Micrographia: Or Some Physiological Descriptions of Minute Bodies Made by Magnifying Glasses. With Observations and Inquiries Thereupon. London: Jo. Martyn, and Ja. Allestry … and are to be sold at their shop …, 1665., 1665.
 116.Hu YJ, Wang YD, Tan FQ, Yang WX. Regulation of paracellular permeability: Factors and mechanisms. Mol Biol Rep 40: 6123‐6142, 2013.
 117.Hurst LA, Dunmore BJ, Long L, Crosby A, Al‐Lamki R, Deighton J, Southwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW. TNFalpha drives pulmonary arterial hypertension by suppressing the BMP type‐II receptor and altering NOTCH signalling. Nat Commun 8: 14079, 2017.
 118.Iijima R, Takahashi H, Namme R, Ikegami S, Yamazaki M. Novel biological function of sialic acid (N‐acetylneuraminic acid) as a hydrogen peroxide scavenger. FEBS Lett 561: 163‐166, 2004.
 119.Ikonomidis I, Pavlidis G, Thymis J, Birba D, Kalogeris A, Kousathana F, Kountouri A, Balampanis K, Parissis J, Andreadou I, Katogiannis K, Dimitriadis G, Bamias A, Iliodromitis E, Lambadiari V. Effects of glucagon‐like peptide‐1 receptor agonists, sodium‐glucose cotransporter‐2 inhibitors, and their combination on endothelial glycocalyx, arterial function, and myocardial work index in patients with type 2 diabetes mellitus after 12‐month treatment. J Am Heart Assoc 9: e015716, 2020.
 120.Ikonomidis I, Voumvourakis A, Makavos G, Triantafyllidi H, Pavlidis G, Katogiannis K, Benas D, Vlastos D, Trivilou P, Varoudi M, Parissis J, Iliodromitis E, Lekakis J. Association of impaired endothelial glycocalyx with arterial stiffness, coronary microcirculatory dysfunction, and abnormal myocardial deformation in untreated hypertensives. J Clin Hypertens 20: 672‐679, 2018.
 121.Insull W Jr. The pathology of atherosclerosis: Plaque development and plaque responses to medical treatment. Am J Med 122: S3‐S14, 2009.
 122.Iring A, Jin YJ, Albarran‐Juarez J, Siragusa M, Wang S, Dancs PT, Nakayama A, Tonack S, Chen M, Kunne C, Sokol AM, Gunther S, Martinez A, Fleming I, Wettschureck N, Graumann J, Weinstein LS, Offermanns S. Shear stress‐induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure. J Clin Invest 130: 2775‐2791, 2019.
 123.Itano N, Sawai T, Yoshida M, Lenas P, Yamada Y, Imagawa M, Shinomura T, Hamaguchi M, Yoshida Y, Ohnuki Y, Miyauchi S, Spicer AP, McDonald JA, Kimata K. Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274: 25085‐25092, 1999.
 124.Ito S. Form and function of the glycocalyx on free cell surfaces. Philos Trans R Soc Lond Ser B Biol Sci 268: 55‐66, 1974.
 125.Jha JC, Watson AMD, Mathew G, de Vos LC, Jandeleit‐Dahm K. The emerging role of NADPH oxidase NOX5 in vascular disease. Clin Sci (Lond) 131: 981‐990, 2017.
 126.Johnson JL. Metalloproteinases in atherosclerosis. Eur J Pharmacol 816: 93‐106, 2017.
 127.Jung B, Obinata H, Galvani S, Mendelson K, Ding BS, Skoura A, Kinzel B, Brinkmann V, Rafii S, Evans T, Hla T. Flow‐regulated endothelial S1P receptor‐1 signaling sustains vascular development. Dev Cell 23: 600‐610, 2012.
 128.Kang H, Wu Q, Sun A, Liu X, Fan Y, Deng X. Cancer cell glycocalyx and its significance in cancer progression. Int J Mol Sci 19: 1‐23, 2018.
 129.Karousou E, Kamiryo M, Skandalis SS, Ruusala A, Asteriou T, Passi A, Yamashita H, Hellman U, Heldin CH, Heldin P. The activity of hyaluronan synthase 2 is regulated by dimerization and ubiquitination. J Biol Chem 285: 23647‐23654, 2010.
 130.Kataoka H, Ushiyama A, Kawakami H, Akimoto Y, Matsubara S, Iijima T. Fluorescent imaging of endothelial glycocalyx layer with wheat germ agglutinin using intravital microscopy. Microsc Res Tech 79: 31‐37, 2016.
 131.Kawahara R, Granato DC, Yokoo S, Domingues RR, Trindade DM, Paes Leme AF. Mass spectrometry‐based proteomics revealed Glypican‐1 as a novel ADAM17 substrate. J Proteome 151: 53‐65, 2017.
 132.Kawamura S, Sato I, Wada T, Yamaguchi K, Li Y, Li D, Zhao X, Ueno S, Aoki H, Tochigi T, Kuwahara M, Kitamura T, Takahashi K, Moriya S, Miyagi T. Plasma membrane‐associated sialidase (NEU3) regulates progression of prostate cancer to androgen‐independent growth through modulation of androgen receptor signaling. Cell Death Differ 19: 170‐179, 2012.
 133.Kefauver JM, Ward AB, Patapoutian A. Discoveries in structure and physiology of mechanically activated ion channels. Nature 587: 567‐576, 2020.
 134.Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology 121: 1‐14, 2007.
 135.Kincses A, Santa‐Maria AR, Walter FR, Der L, Horanyi N, Lipka DV, Valkai S, Deli MA, Der A. A chip device to determine surface charge properties of confluent cell monolayers by measuring streaming potential. Lab Chip 20: 3792‐3805, 2020.
 136.Knoepp F, Ashley Z, Barth D, Baldin JP, Jennings M, Kazantseva M, Saw EL, Katare R, Alvarez de la Rosa D, Weissmann N, Fronius M. Shear force sensing of epithelial Na(+) channel (ENaC) relies on N‐glycosylated asparagines in the palm and knuckle domains of alphaENaC. Proc Natl Acad Sci U S A 117: 717‐726, 2020.
 137.Koganti R, Suryawanshi R, Shukla D. Heparanase, cell signaling, and viral infections. Cell Mol Life Sci 77: 5059‐5077, 2020.
 138.Kolarova H, Ambruzova B, Svihalkova Sindlerova L, Klinke A, Kubala L. Modulation of endothelial glycocalyx structure under inflammatory conditions. Mediat Inflamm 2014: 694312, 2014.
 139.Kong X, Chen L, Ye P, Wang Z, Zhang J, Ye F, Chen S. The role of HYAL2 in LSS‐induced glycocalyx impairment and the PKA‐mediated decrease in eNOS‐Ser‐633 phosphorylation and nitric oxide production. Mol Biol Cell 27: 3972‐3979, 2016.
 140.Koo A, Dewey CF Jr, Garcia‐Cardena G. Hemodynamic shear stress characteristic of atherosclerosis‐resistant regions promotes glycocalyx formation in cultured endothelial cells. Am J Physiol Cell Physiol 304: C137‐C146, 2013.
 141.Kowalski GM, Carey AL, Selathurai A, Kingwell BA, Bruce CR. Plasma sphingosine‐1‐phosphate is elevated in obesity. PLoS One 8: e72449, 2013.
 142.Krystel‐Whittemore M, Dileepan KN, Wood JG. Mast cell: a multi‐functional master cell. Front Immunol 6: 620, 2015.
 143.Kumagai R, Lu X, Kassab GS. Role of glycocalyx in flow‐induced production of nitric oxide and reactive oxygen species. Free Radic Biol Med 47: 600‐607, 2009.
 144.Kumase F, Morizane Y, Mohri S, Takasu I, Ohtsuka A, Ohtsuki H. Glycocalyx degradation in retinal and choroidal capillary endothelium in rats with diabetes and hypertension. Acta Med Okayama 64: 277‐283, 2010.
 145.Kurano M, Yatomi Y. Sphingosine 1‐phosphate and atherosclerosis. J Atheroscler Thromb 25: 16‐26, 2018.
 146.Kutuzov N, Flyvbjerg H, Lauritzen M. Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood‐brain barrier. Proc Natl Acad Sci U S A 115: E9429‐E9438, 2018.
 147.Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB. The vascular smooth muscle cell in arterial pathology: A cell that can take on multiple roles. Cardiovasc Res 95: 194‐204, 2012.
 148.Landolfo M, Borghi C. Hyperuricaemia and vascular risk: The debate continues. Curr Opin Cardiol 34: 399‐405, 2019.
 149.Langjahr P, Diaz‐Jimenez D, De la Fuente M, Rubio E, Golenbock D, Bronfman FC, Quera R, Gonzalez MJ, Hermoso MA. Metalloproteinase‐dependent TLR2 ectodomain shedding is involved in soluble toll‐like receptor 2 (sTLR2) production. PLoS One 9: e104624, 2014.
 150.Lassegue B, San Martin A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 110: 1364‐1390, 2012.
 151.Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, Dennis JW. Complex N‐glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129: 123‐134, 2007.
 152.Le Roux AL, Quiroga X, Walani N, Arroyo M, Roca‐Cusachs P. The plasma membrane as a mechanochemical transducer. Philos Trans R Soc Lond Ser B Biol Sci 374: 20180221, 2019.
 153.Lee AC, Lam JK, Shiu SW, Wong Y, Betteridge DJ, Tan KC. Serum level of soluble receptor for advanced glycation end products is associated with a disintegrin and metalloproteinase 10 in type 1 diabetes. PLoS One 10: e0137330, 2015.
 154.Lee DH, Dane MJ, van den Berg BM, Boels MG, van Teeffelen JW, de Mutsert R, den Heijer M, Rosendaal FR, van der Vlag J, van Zonneveld AJ, Vink H, Rabelink TJ. Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion. PLoS One 9: e96477, 2014.
 155.Lee KS, Kim SR, Park SJ, Min KH, Lee KY, Choe YH, Park SY, Chai OH, Zhang X, Song CH, Lee YC. Mast cells can mediate vascular permeability through regulation of the PI3K‐HIF‐1alpha‐VEGF axis. Am J Respir Crit Care Med 178: 787‐797, 2008.
 156.Lee SH, Fujioka S, Takahashi R, Oe T. Angiotensin II‐induced oxidative stress in human endothelial cells: Modification of cellular molecules through lipid peroxidation. Chem Res Toxicol 32: 1412‐1422, 2019.
 157.Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I, Kremastinos D, Landmesser U, Protogerou A, Stefanadis C, Tousoulis D, Vassalli G, Vink H, Werner N, Wilkinson I, Vlachopoulos C. Methods for evaluating endothelial function: A position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur J Cardiovasc Prev Rehabil 18: 775‐789, 2011.
 158.Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res 87: 198‐210, 2010.
 159.Levy‐Adam F, Feld S, Cohen‐Kaplan V, Shteingauz A, Gross M, Arvatz G, Naroditsky I, Ilan N, Doweck I, Vlodavsky I. Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity. J Biol Chem 285: 28010‐28019, 2010.
 160.Li DQ, Shang TY, Kim HS, Solomon A, Lokeshwar BL, Pflugfelder SC. Regulated expression of collagenases MMP‐1, ‐8, and ‐13 and stromelysins MMP‐3, ‐10, and ‐11 by human corneal epithelial cells. Invest Ophthalmol Vis Sci 44: 2928‐2936, 2003.
 161.Li H, Horke S, Forstermann U. Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis 237: 208‐219, 2014.
 162.Li Q, Youn JY, Cai H. Mechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertension. J Hypertens 33: 1128‐1136, 2015.
 163.Li Z, Wu N, Wang J, Zhang Q. Roles of endovascular calyx related enzymes in endothelial dysfunction and diabetic vascular complications. Front Pharmacol 11: 590614, 2020.
 164.Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della‐Morte D, Gargiulo G, Testa G, Cacciatore F, Bonaduce D, Abete P. Oxidative stress, aging, and diseases. Clin Interv Aging 13: 757‐772, 2018.
 165.Linton MRF, Yancey PG, Davies SS, Jerome WG, Linton EF, Song WL, Doran AC, Vickers KC. The role of lipids and lipoproteins in atherosclerosis. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland J, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, editors. Endotext. South Dartmouth, MA: MDtext.com, Inc., 2000.
 166.Lipowsky HH. The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases. Ann Biomed Eng 40: 840‐848, 2012.
 167.Lipowsky HH, Lescanic A. The effect of doxycycline on shedding of the glycocalyx due to reactive oxygen species. Microvasc Res 90: 80‐85, 2013.
 168.Lipphardt M, Song JW, Goligorsky MS. Sirtuin 1 and endothelial glycocalyx. Pflugers Arch 472: 991‐1002, 2020.
 169.Liu W, Liu B, Liu S, Zhang J, Lin S. Sphingosine‐1‐phosphate receptor 2 mediates endothelial cells dysfunction by PI3K‐Akt pathway under high glucose condition. Eur J Pharmacol 776: 19‐25, 2016.
 170.Lombard J. Once upon a time the cell membranes: 175 years of cell boundary research. Biol Direct 9: 32, 2014.
 171.Loufrani L, Henrion D. Role of the cytoskeleton in flow (shear stress)‐induced dilation and remodeling in resistance arteries. Med Biol Eng Comput 46: 451‐460, 2008.
 172.Lowe DT. Nitric oxide dysfunction in the pathophysiology of preeclampsia. Nitric Oxide 4: 441‐458, 2000.
 173.Machin DR, Bloom SI, Campbell RA, Phuong TTT, Gates PE, Lesniewski LA, Rondina MT, Donato AJ. Advanced age results in a diminished endothelial glycocalyx. Am J Physiol Heart Circ Physiol 315: H531‐H539, 2018.
 174.Mack JJ, Mosqueiro TS, Archer BJ, Jones WM, Sunshine H, Faas GC, Briot A, Aragon RL, Su T, Romay MC, McDonald AI, Kuo CH, Lizama CO, Lane TF, Zovein AC, Fang Y, Tarling EJ, de Aguiar Vallim TQ, Navab M, Fogelman AM, Bouchard LS, Iruela‐Arispe ML. NOTCH1 is a mechanosensor in adult arteries. Nat Commun 8: 1620, 2017.
 175.Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: A historical perspective. Lancet 383: 999‐1008, 2014.
 176.Mahmoud M, Mayer M, Cancel LM, Bartosch AM, Mathews R, Tarbell JM. The glycocalyx core protein Glypican 1 protects vessel wall endothelial cells from stiffness‐mediated dysfunction and disease. Cardiovasc Res, 2020.
 177.Majesky MW, Dong XR, Hoglund V, Mahoney WM Jr, Daum G. The adventitia: A dynamic interface containing resident progenitor cells. Arterioscler Thromb Vasc Biol 31: 1530‐1539, 2011.
 178.Majesky MW, Dong XR, Regan JN, Hoglund VJ. Vascular smooth muscle progenitor cells: Building and repairing blood vessels. Circ Res 108: 365‐377, 2011.
 179.Malanovic N, Lohner K. Gram‐positive bacterial cell envelopes: The impact on the activity of antimicrobial peptides. Biochim Biophys Acta 1858: 936‐946, 2016.
 180.Maroski J, Vorderwulbecke BJ, Fiedorowicz K, Da Silva‐Azevedo L, Siegel G, Marki A, Pries AR, Zakrzewicz A. Shear stress increases endothelial hyaluronan synthase 2 and hyaluronan synthesis especially in regard to an atheroprotective flow profile. Exp Physiol 96: 977‐986, 2011.
 181.Marso SP, Daniels GH, Brown‐Frandsen K, Kristensen P, Mann JFE, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375: 311‐322, 2016.
 182.Martinez‐Lemus LA. The dynamic structure of arterioles. Basic Clin Pharmacol Toxicol 110: 5‐11, 2012.
 183.Martinez‐Lemus LA, Hill MA, Meininger GA. The plastic nature of the vascular wall: A continuum of remodeling events contributing to control of arteriolar diameter and structure. Physiology (Bethesda) 24 2009.
 184.Mazor R, Friedmann‐Morvinski D, Alsaigh T, Kleifeld O, Kistler EB, Rousso‐Noori L, Huang C, Li JB, Verma IM, Schmid‐Schonbein GW. Cleavage of the leptin receptor by matrix metalloproteinase‐2 promotes leptin resistance and obesity in mice. Sci Transl Med 10: 1‐11, 2018.
 185.McDonald B, Kubes P. Interactions between CD44 and hyaluronan in leukocyte trafficking. Front Immunol 6: 68, 2015.
 186.Megens RT, Reitsma S, Schiffers PH, Hilgers RH, De Mey JG, Slaaf DW, oude Egbrink MG, van Zandvoort MA. Two‐photon microscopy of vital murine elastic and muscular arteries. Combined structural and functional imaging with subcellular resolution. J Vasc Res 44: 87‐98, 2007.
 187.Mehdi MM, Singh P, Rizvi SI. Erythrocyte sialic acid content during aging in humans: Correlation with markers of oxidative stress. Dis Markers 32: 179‐186, 2012.
 188.Mehta V, Pang KL, Rozbesky D, Nather K, Keen A, Lachowski D, Kong Y, Karia D, Ameismeier M, Huang J, Fang Y, Del Rio Hernandez A, Reader JS, Jones EY, Tzima E. The guidance receptor plexin D1 is a mechanosensor in endothelial cells. Nature 578: 290‐295, 2020.
 189.Michen B, Graule T. Isoelectric points of viruses. J Appl Microbiol 109: 388‐397, 2010.
 190.Mitchell GF. Arterial stiffness: Insights from Framingham and Iceland. Curr Opin Nephrol Hypertens 24: 1‐7, 2015.
 191.Mitra R, O'Neil GL, Harding IC, Cheng MJ, Mensah SA, Ebong EE. Glycocalyx in atherosclerosis‐relevant endothelium function and as a therapeutic target. Curr Atheroscler Rep 19: 63, 2017.
 192.Miyagi T. Aberrant expression of sialidase and cancer progression. Proc Jpn Acad Ser B Phys Biol Sci 84: 407‐418, 2008.
 193.Miyagi T, Yamaguchi K. Mammalian sialidases: Physiological and pathological roles in cellular functions. Glycobiology 22: 880‐896, 2012.
 194.Mochizuki S, Vink H, Hiramatsu O, Kajita T, Shigeto F, Spaan JA, Kajiya F. Role of hyaluronic acid glycosaminoglycans in shear‐induced endothelium‐derived nitric oxide release. Am J Physiol Heart Circ Physiol 285: H722‐H726, 2003.
 195.Mockl L. The emerging role of the mammalian glycocalyx in functional membrane organization and immune system regulation. Front Cell Dev Biol 8: 253, 2020.
 196.Mockl L, Pedram K, Roy AR, Krishnan V, Gustavsson AK, Dorigo O, Bertozzi CR, Moerner WE. Quantitative super‐resolution microscopy of the mammalian glycocalyx. Dev Cell 50: 57.e56‐72.e56, 2019.
 197.Molvarec A, Szarka A, Walentin S, Beko G, Karadi I, Prohaszka Z, Rigo J Jr. Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia. Reprod Biol Endocrinol 9: 124, 2011.
 198.Montaner J, Ramiro L, Simats A, Hernandez‐Guillamon M, Delgado P, Bustamante A, Rosell A. Matrix metalloproteinases and ADAMs in stroke. Cell Mol Life Sci 76: 3117‐3140, 2019.
 199.Monti E, Bonten E, D'Azzo A, Bresciani R, Venerando B, Borsani G, Schauer R, Tettamanti G. Sialidases in vertebrates: A family of enzymes tailored for several cell functions. Adv Carbohydr Chem Biochem 64: 403‐479, 2010.
 200.Monzon ME, Fregien N, Schmid N, Falcon NS, Campos M, Casalino‐Matsuda SM, Forteza RM. Reactive oxygen species and hyaluronidase 2 regulate airway epithelial hyaluronan fragmentation. J Biol Chem 285: 26126‐26134, 2010.
 201.Moseley R, Waddington RJ, Embery G. Degradation of glycosaminoglycans by reactive oxygen species derived from stimulated polymorphonuclear leukocytes. Biochim Biophys Acta 1362: 221‐231, 1997.
 202.Mui KL, Chen CS, Assoian RK. The mechanical regulation of integrin‐cadherin crosstalk organizes cells, signaling and forces. J Cell Sci 129: 1093‐1100, 2016.
 203.Mukai S, Takaki T, Nagumo T, Sano M, Kang D, Takimoto M, Honda K. Three‐dimensional electron microscopy for endothelial glycocalyx observation using Alcian blue with silver enhancement. Med Mol Morphol 54: 95‐107, 2020.
 204.Mulivor AW, Lipowsky HH. Inhibition of glycan shedding and leukocyte‐endothelial adhesion in postcapillary venules by suppression of matrixmetalloprotease activity with doxycycline. Microcirculation 16: 657‐666, 2009.
 205.Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines 6: 1‐10, 2019.
 206.Myers TJ, Brennaman LH, Stevenson M, Higashiyama S, Russell WE, Lee DC, Sunnarborg SW. Mitochondrial reactive oxygen species mediate GPCR‐induced TACE/ADAM17‐dependent transforming growth factor‐alpha shedding. Mol Biol Cell 20: 5236‐5249, 2009.
 207.Nadir Y, Brenner B. Heparanase procoagulant effects and inhibition by heparins. Thromb Res 125 Suppl 2: S72‐S76, 2010.
 208.Nassimizadeh M, Ashrafian H, Drury NE, Howell NJ, Digby J, Pagano D, Frenneaux MP, Born GV. Reduced negative surface charge on arterial endothelium explains accelerated atherosclerosis in type 2 diabetic patients. Diabetes Vasc Dis Res 7: 213‐215, 2010.
 209.Natoni A, Macauley MS, O'Dwyer ME. Targeting selectins and their ligands in cancer. Front Oncol 6: 93, 2016.
 210.Natori Y, Ohkura N, Nasui M, Atsumi G, Kihara‐Negishi F. Acidic sialidase activity is aberrant in obese and diabetic mice. Biol Pharm Bull 36: 1027‐1031, 2013.
 211.Nieuwdorp M, Holleman F, de Groot E, Vink H, Gort J, Kontush A, Chapman MJ, Hutten BA, Brouwer CB, Hoekstra JB, Kastelein JJ, Stroes ES. Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis. Diabetologia 50: 1288‐1293, 2007.
 212.Nieuwdorp M, Mooij HL, Kroon J, Atasever B, Spaan JA, Ince C, Holleman F, Diamant M, Heine RJ, Hoekstra JB, Kastelein JJ, Stroes ES, Vink H. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55: 1127‐1132, 2006.
 213.Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, Meijers JC, Holleman F, Hoekstra JB, Vink H. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55: 480‐486, 2006.
 214.Noble PW, McKee CM, Cowman M, Shin HS. Hyaluronan fragments activate an NF‐kappa B/I‐kappa B alpha autoregulatory loop in murine macrophages. J Exp Med 183: 2373‐2378, 1996.
 215.Oberleithner H, Riethmuller C, Schillers H, MacGregor GA, de Wardener HE, Hausberg M. Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc Natl Acad Sci U S A 104: 16281‐16286, 2007.
 216.O'Callaghan R, Job KM, Dull RO, Hlady V. Stiffness and heterogeneity of the pulmonary endothelial glycocalyx measured by atomic force microscopy. Am J Physiol Lung Cell Mol Physiol 301: L353‐L360, 2011.
 217.Oh JK, Yegin Y, Yang F, Zhang M, Li J, Huang S, Verkhoturov SV, Schweikert EA, Perez‐Lewis K, Scholar EA, Taylor TM, Castillo A, Cisneros‐Zevallos L, Min Y, Akbulut M. The influence of surface chemistry on the kinetics and thermodynamics of bacterial adhesion. Sci Rep 8: 17247, 2018.
 218.Ohkawa R, Nakamura K, Okubo S, Hosogaya S, Ozaki Y, Tozuka M, Osima N, Yokota H, Ikeda H, Yatomi Y. Plasma sphingosine‐1‐phosphate measurement in healthy subjects: Close correlation with red blood cell parameters. Ann Clin Biochem 45: 356‐363, 2008.
 219.Olde Engberink RH, Rorije NM, van der Homan, Heide JJ, van den Born BJ, Vogt L. Role of the vascular wall in sodium homeostasis and salt sensitivity. J Am Soc Nephrol 26: 777‐783, 2015.
 220.Oltean S, Qiu Y, Ferguson JK, Stevens M, Neal C, Russell A, Kaura A, Arkill KP, Harris K, Symonds C, Lacey K, Wijeyaratne L, Gammons M, Wylie E, Hulse RP, Alsop C, Cope G, Damodaran G, Betteridge KB, Ramnath R, Satchell SC, Foster RR, Ballmer‐Hofer K, Donaldson LF, Barratt J, Baelde HJ, Harper SJ, Bates DO, Salmon AH. Vascular endothelial growth factor‐A165b is protective and restores endothelial glycocalyx in diabetic nephropathy. J Am Soc Nephrol 26: 1889‐1904, 2015.
 221.Onclinx C, Dogne S, Jadin L, Andris F, Grandfils C, Jouret F, Mullier F, Flamion B. Deficiency in mouse hyaluronidase 2: A new mechanism of chronic thrombotic microangiopathy. Haematologica 100: 1023‐1030, 2015.
 222.Ono S, Egawa G, Kabashima K. Regulation of blood vascular permeability in the skin. Inflamm Regen 37: 11, 2017.
 223.Opal SM, Kessler CM, Roemisch J, Knaub S. Antithrombin, heparin, and heparan sulfate. Crit Care Med 30: S325‐S331, 2002.
 224.Pahakis MY, Kosky JR, Dull RO, Tarbell JM. The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress. Biochem Biophys Res Commun 355: 228‐233, 2007.
 225.Pahwa R, Nallasamy P, Jialal I. Toll‐like receptors 2 and 4 mediate hyperglycemia induced macrovascular aortic endothelial cell inflammation and perturbation of the endothelial glycocalyx. J Diabetes Complicat 30: 563‐572, 2016.
 226.Paravicini TM, Touyz RM. NADPH oxidases, reactive oxygen species, and hypertension: Clinical implications and therapeutic possibilities. Diabetes Care 31 Suppl 2: S170‐S180, 2008.
 227.Paulson JC, Kawasaki N. Sialidase inhibitors DAMPen sepsis. Nat Biotechnol 29: 406‐407, 2011.
 228.Pessentheiner AR, Ducasa GM, Gordts P. Proteoglycans in obesity‐associated metabolic dysfunction and meta‐inflammation. Front Immunol 11: 769, 2020.
 229.Peterson S, Liu J. Deciphering mode of action of heparanase using structurally defined oligosaccharides. J Biol Chem 287: 34836‐34843, 2012.
 230.Piccoli M, Conforti E, Varrica A, Ghiroldi A, Cirillo F, Resmini G, Pluchinotta F, Tettamanti G, Giamberti A, Frigiola A, Anastasia L. NEU3 sialidase role in activating HIF‐1alpha in response to chronic hypoxia in cyanotic congenital heart patients. Int J Cardiol 230: 6‐13, 2017.
 231.Pollack W, Reckel RP. A reappraisal of the forces involved in hemagglutination. Int Arch Allergy Appl Immunol 54: 29‐42, 1977.
 232.Proia RL, Hla T. Emerging biology of sphingosine‐1‐phosphate: Its role in pathogenesis and therapy. J Clin Invest 125: 1379‐1387, 2015.
 233.Psefteli PM, Kitscha P, Vizcay G, Fleck R, Chapple SJ, Mann GE, Fowler M, Siow RC. Glycocalyx sialic acids regulate Nrf2‐mediated signaling by fluid shear stress in human endothelial cells. Redox Biol 38: 101816, 2021.
 234.Pshezhetsky AV, Richard C, Michaud L, Igdoura S, Wang S, Elsliger MA, Qu J, Leclerc D, Gravel R, Dallaire L, Potier M. Cloning, expression and chromosomal mapping of human lysosomal sialidase and characterization of mutations in sialidosis. Nat Genet 15: 316‐320, 1997.
 235.Puerta‐Guardo H, Glasner DR, Harris E. Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability. PLoS Pathog 12: e1005738, 2016.
 236.Ra HJ, Parks WC. Control of matrix metalloproteinase catalytic activity. Matrix Biol 26: 587‐596, 2007.
 237.Rahbar E, Cardenas JC, Baimukanova G, Usadi B, Bruhn R, Pati S, Ostrowski SR, Johansson PI, Holcomb JB, Wade CE. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J Transl Med 13: 117, 2015.
 238.Rahman MM, Hirokawa T, Tsuji D, Tsukimoto J, Hitaoka S, Yoshida T, Chuman H, Itoh K. Novel pH‐dependent regulation of human cytosolic sialidase 2 (NEU2) activities by siastatin B and structural prediction of NEU2/siastatin B complex. Biochem Biophys Rep 4: 234‐242, 2015.
 239.Rai S, Nejadhamzeeigilani Z, Gutowski NJ, Whatmore JL. Loss of the endothelial glycocalyx is associated with increased E‐selectin mediated adhesion of lung tumour cells to the brain microvascular endothelium. J Exp Clin Cancer Res 34: 105, 2015.
 240.Reitsma S, Oude Egbrink MG, Heijnen VV, Megens RT, Engels W, Vink H, Slaaf DW, van Zandvoort MA. Endothelial glycocalyx thickness and platelet‐vessel wall interactions during atherogenesis. Thromb Haemost 106: 939‐946, 2011.
 241.Reitsma S, oude Egbrink MG, Vink H, van den Berg BM, Passos VL, Engels W, Slaaf DW, van Zandvoort MA. Endothelial glycocalyx structure in the intact carotid artery: A two‐photon laser scanning microscopy study. J Vasc Res 48: 297‐306, 2011.
 242.Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454: 345‐359, 2007.
 243.Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108 (Pt 6): 2369‐2379, 1995.
 244.Rodriguez‐Walker M, Daniotti JL. Human sialidase Neu 3 is S‐acylated and behaves like an integral membrane protein. Sci Rep 7: 4167, 2017.
 245.Rose F, Zeller SA, Chakraborty T, Domann E, Machleidt T, Kronke M, Seeger W, Grimminger F, Sibelius U. Human endothelial cell activation and mediator release in response to Listeria monocytogenes virulence factors. Infect Immun 69: 897‐905, 2001.
 246.Rouger P, Salmon C. Tissue distribution and development of blood group antigens. Rev Fr Transfus Immunohematol 25: 643‐656, 1982.
 247.Rovas A, Lukasz AH, Vink H, Urban M, Sackarnd J, Pavenstadt H, Kumpers P. Bedside analysis of the sublingual microvascular glycocalyx in the emergency room and intensive care unit—the GlycoNurse study. Scand J Trauma Resusc Emerg Med 26: 16, 2018.
 248.Rovas A, Seidel LM, Vink H, Pohlkotter T, Pavenstadt H, Ertmer C, Hessler M, Kumpers P. Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions in resuscitated sepsis. Crit Care 23: 260, 2019.
 249.Salazar G. NADPH oxidases and mitochondria in vascular senescence. Int J Mol Sci 19: 1‐21, 2018.
 250.Salmon AH, Ferguson JK, Burford JL, Gevorgyan H, Nakano D, Harper SJ, Bates DO, Peti‐Peterdi J. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J Am Soc Nephrol 23: 1339‐1350, 2012.
 251.Samraj AN, Laubli H, Varki N, Varki A. Involvement of a non‐human sialic acid in human cancer. Front Oncol 4: 33, 2014.
 252.Sanchez T, Skoura A, Wu MT, Casserly B, Harrington EO, Hla T. Induction of vascular permeability by the sphingosine‐1‐phosphate receptor–2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol 27: 1312‐1318, 2007.
 253.Sandow SL, Gzik DJ, Lee RM. Arterial internal elastic lamina holes: Relationship to function? J Anat 214: 258‐266, 2009.
 254.Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol 3: 1‐33, 2011.
 255.Sasaki A, Hata K, Suzuki S, Sawada M, Wada T, Yamaguchi K, Obinata M, Tateno H, Suzuki H, Miyagi T. Overexpression of plasma membrane‐associated sialidase attenuates insulin signaling in transgenic mice. J Biol Chem 278: 27896‐27902, 2003.
 256.Schmidt CQ, Hipgrave Ederveen AL, Harder MJ, Wuhrer M, Stehle T, Blaum BS. Biophysical analysis of sialic acid recognition by the complement regulator Factor H. Glycobiology 28: 765‐773, 2018.
 257.Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, Zemans RL, Bowman JC, Koyanagi DE, Yunt ZX, Smith LP, Cheng SS, Overdier KH, Thompson KR, Geraci MW, Douglas IS, Pearse DB, Tuder RM. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18: 1217‐1223, 2012.
 258.Schneck E, Schubert T, Konovalov OV, Quinn BE, Gutsmann T, Brandenburg K, Oliveira RG, Pink DA, Tanaka M. Quantitative determination of ion distributions in bacterial lipopolysaccharide membranes by grazing‐incidence X‐ray fluorescence. Proc Natl Acad Sci U S A 107: 9147‐9151, 2010.
 259.Seligman SP, Buyon JP, Clancy RM, Young BK, Abramson SB. The role of nitric oxide in the pathogenesis of preeclampsia. Am J Obstet Gynecol 171: 944‐948, 1994.
 260.Sena CM, Pereira AM, Seica R. Endothelial dysfunction—A major mediator of diabetic vascular disease. Biochim Biophys Acta 1832: 2216‐2231, 2013.
 261.Serroukh Y, Djebara S, Lelubre C, Zouaoui Boudjeltia K, Biston P, Piagnerelli M. Alterations of the erythrocyte membrane during sepsis. Crit Care Res Pract 2012: 702956, 2012.
 262.Sharman JE, LaGerche A. Exercise blood pressure: Clinical relevance and correct measurement. J Hum Hypertens 29: 351‐358, 2015.
 263.Shiga K, Takahashi K, Sato I, Kato K, Saijo S, Moriya S, Hosono M, Miyagi T. Upregulation of sialidase NEU3 in head and neck squamous cell carcinoma associated with lymph node metastasis. Cancer Sci 106: 1544‐1553, 2015.
 264.Shivananda Nayak B, Duncan H, Lalloo S, Maraj K, Matmungal V, Matthews F, Prajapati B, Samuel R, Sylvester P. Correlation of microalbumin and sialic acid with anthropometric variables in type 2 diabetic patients with and without nephropathy. Vasc Health Risk Manag 4: 243‐247, 2008.
 265.Shriver Z, Capila I, Venkataraman G, Sasisekharan R. Heparin and heparan sulfate: Analyzing structure and microheterogeneity. Handb Exp Pharmacol 207: 159‐176, 2012.
 266.Shurer CR, Kuo JC, Roberts LM, Gandhi JG, Colville MJ, Enoki TA, Pan H, Su J, Noble JM, Hollander MJ, O'Donnell JP, Yin R, Pedram K, Mockl L, Kourkoutis LF, Moerner WE, Bertozzi CR, Feigenson GW, Reesink HL, Paszek MJ. Physical principles of membrane shape regulation by the glycocalyx. Cell 177: 1757‐1770, 2019.
 267.Shworak NW, Kobayashi T, de Agostini A, Smits NC. Anticoagulant heparan sulfate to not clot—or not? Prog Mol Biol Transl Sci 93: 153‐178, 2010.
 268.Singh A, Ramnath RD, Foster RR, Wylie EC, Friden V, Dasgupta I, Haraldsson B, Welsh GI, Mathieson PW, Satchell SC. Reactive oxygen species modulate the barrier function of the human glomerular endothelial glycocalyx. PLoS One 8: e55852, 2013.
 269.Singleton PA, Dudek SM, Ma SF, Garcia JG. 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.
 270.Stroev PV, Hoskins PR, Easson WJ. Distribution of wall shear rate throughout the arterial tree: A case study. Atherosclerosis 191: 276‐280, 2007.
 271.Talsma DT, Poppelaars F, Dam W, Meter‐Arkema AH, Vives RR, Gal P, Boons GJ, Chopra P, Naggi A, Seelen MA, Berger SP, Daha MR, Stegeman CA, van den Born J, Consortium C. MASP‐2 is a heparin‐binding protease; identification of blocking oligosaccharides. Front Immunol 11: 732, 2020.
 272.Tarbell JM, Shi ZD. Effect of the glycocalyx layer on transmission of interstitial flow shear stress to embedded cells. Biomech Model Mechanobiol 12: 111‐121, 2013.
 273.Targosz‐Korecka M, Jaglarz M, Malek‐Zietek KE, Gregorius A, Zakrzewska A, Sitek B, Rajfur Z, Chlopicki S, Szymonski M. AFM‐based detection of glycocalyx degradation and endothelial stiffening in the db/db mouse model of diabetes. Sci Rep 7: 15951, 2017.
 274.Tarhouni K, Guihot AL, Vessieres E, Toutain B, Procaccio V, Grimaud L, Loufrani L, Lenfant F, Arnal JF, Henrion D. Determinants of flow‐mediated outward remodeling in female rodents: Respective roles of age, estrogens, and timing. Arterioscler Thromb Vasc Biol 34: 1281‐1289, 2014.
 275.Tarpey MM, Fridovich I. Methods of detection of vascular reactive species: Nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite. Circ Res 89: 224‐236, 2001.
 276.Tavianatou AG, Caon I, Franchi M, Piperigkou Z, Galesso D, Karamanos NK. Hyaluronan: Molecular size‐dependent signaling and biological functions in inflammation and cancer. FEBS J 286: 2883‐2908, 2019.
 277.Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID‐19: The vasculature unleashed. Nat Rev Immunol 20: 389‐391, 2020.
 278.Tringali C, Fiorilli A, Venerando B, Tettamanti G. Different behavior of ghost‐linked acidic and neutral sialidases during human erythrocyte ageing. Glycoconj J 18: 407‐418, 2001.
 279.Tsioufis C, Bafakis I, Kasiakogias A, Stefanadis C. The role of matrix metalloproteinases in diabetes mellitus. Curr Top Med Chem 12: 1159‐1165, 2012.
 280.Tucker WD, Arora Y, Mahajan K. Anatomy, Blood Vessels. In: StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2021, StatPearls Publishing LLC., 2021.
 281.Tukijan F, Chandrakanthan M, Nguyen LN. The signalling roles of sphingosine‐1‐phosphate derived from red blood cells and platelets. Br J Pharmacol 175: 3741‐3746, 2018.
 282.Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, Wainford RD, Williams B, Schutte AE. 2020 International society of hypertension global hypertension practice guidelines. Hypertension 75: 1334‐1357, 2020.
 283.Vajaria BN, Patel KR, Begum R, Patel PS. Sialylation: An avenue to target cancer cells. Pathol Oncol Res 22: 443‐447, 2016.
 284.van de Wall S, Santegoets KCM, van Houtum EJH, Bull C, Adema GJ. Sialoglycans and siglecs can shape the tumor immune microenvironment. Trends Immunol 41: 274‐285, 2020.
 285.van den Berg BM, Spaan JA, Rolf TM, Vink H. Atherogenic region and diet diminish glycocalyx dimension and increase intima‐to‐media ratios at murine carotid artery bifurcation. Am J Physiol Heart Circ Physiol 290: H915‐H920, 2006.
 286.van den Berg BM, Vink H, Spaan JA. The endothelial glycocalyx protects against myocardial edema. Circ Res 92: 592‐594, 2003.
 287.van den Berg BM, Wang G, Boels MGS, Avramut MC, Jansen E, Sol W, Lebrin F, van Zonneveld AJ, de Koning EJP, Vink H, Grone HJ, Carmeliet P, van der Vlag J, Rabelink TJ. Glomerular function and structural integrity depend on hyaluronan synthesis by glomerular endothelium. J Am Soc Nephrol 30: 1886‐1897, 2019.
 288.van den Hoven MJ, Waanders F, Rops AL, Kramer AB, van Goor H, Berden JH, Navis G, van der Vlag J. Regulation of glomerular heparanase expression by aldosterone, angiotensin II and reactive oxygen species. Nephrol Dial Transplant 24: 2637‐2645, 2009.
 289.van Haaren PM, VanBavel E, Vink H, Spaan JA. Localization of the permeability barrier to solutes in isolated arteries by confocal microscopy. Am J Physiol Heart Circ Physiol 285: H2848‐H2856, 2003.
 290.Van Teeffelen JW, Brands J, Stroes ES, Vink H. Endothelial glycocalyx: Sweet shield of blood vessels. Trends Cardiovasc Med 17: 101‐105, 2007.
 291.VanTeeffelen JW, Brands J, Jansen C, Spaan JA, Vink H. Heparin impairs glycocalyx barrier properties and attenuates shear dependent vasodilation in mice. Hypertension 50: 261‐267, 2007.
 292.Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Darvill AG, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH, editors. Essentials of Glycobiology. 3rd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2015.
 293.Venkataraman K, Lee Y‐M, Michaud J, Thangada S, Ai Y, Bonkovsky HL, Parikh NS, Habrukowich C, Hla T. Vascular endothelium as a contributor of plasma sphingosine 1‐phosphate. Circ Res 102: 669‐676, 2008.
 294.Vigetti D, Deleonibus S, Moretto P, Karousou E, Viola M, Bartolini B, Hascall VC, Tammi M, De Luca G, Passi A. Role of UDP‐N‐acetylglucosamine (GlcNAc) and O‐GlcNAcylation of hyaluronan synthase 2 in the control of chondroitin sulfate and hyaluronan synthesis. J Biol Chem 287: 35544‐35555, 2012.
 295.Vigetti D, Genasetti A, Karousou E, Viola M, Clerici M, Bartolini B, Moretto P, De Luca G, Hascall VC, Passi A. Modulation of hyaluronan synthase activity in cellular membrane fractions. J Biol Chem 284: 30684‐30694, 2009.
 296.Villalba N, Baby S, Yuan SY. The endothelial glycocalyx as a double‐edged sword in microvascular homeostasis and pathogenesis. Front Cell Dev Biol 9: 711003, 2021.
 297.Vink H, Duling BR. Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. Circ Res 79: 581‐589, 1996.
 298.Vlodavsky I, Blich M, Li JP, Sanderson RD, Ilan N. Involvement of heparanase in atherosclerosis and other vessel wall pathologies. Matrix Biol 32: 241‐251, 2013.
 299.Vlodavsky I, Ilan N, Naggi A, Casu B. Heparanase: Structure, biological functions, and inhibition by heparin‐derived mimetics of heparan sulfate. Curr Pharm Des 13: 2057‐2073, 2007.
 300.Voskoboinik I, Soderholm K, Cotgreave IA. Ascorbate and glutathione homeostasis in vascular smooth muscle cells: Cooperation with endothelial cells. Am J Phys 275: C1031‐C1039, 1998.
 301.Waheed F, Dan Q, Amoozadeh Y, Zhang Y, Tanimura S, Speight P, Kapus A, Szaszi K. Central role of the exchange factor GEF‐H1 in TNF‐alpha‐induced sequential activation of Rac, ADAM17/TACE, and RhoA in tubular epithelial cells. Mol Biol Cell 24: 1068‐1082, 2013.
 302.Wang G, Kostidis S, Tiemeier GL, Sol W, de Vries MR, Giera M, Carmeliet P, van den Berg BM, Rabelink TJ. Shear stress regulation of endothelial glycocalyx structure is determined by glucobiosynthesis. Arterioscler Thromb Vasc Biol 40: 350‐364, 2020.
 303.Wang H, Huang H, Ding SF. Sphingosine‐1‐phosphate promotes the proliferation and attenuates apoptosis of Endothelial progenitor cells via S1PR1/S1PR3/PI3K/Akt pathway. Cell Biol Int. 42 (11): 1492‐1502, 2018.
 304.Wang MH, Hsiao G, Al‐Shabrawey M. Eicosanoids and oxidative stress in diabetic retinopathy. Antioxidants 9: 1‐20, 2020.
 305.Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9: 121‐167, 2007.
 306.Weissgerber TL, Garcia‐Valencia O, Milic NM, Codsi E, Cubro H, Nath MC, White WM, Nath KA, Garovic VD. Early onset preeclampsia is associated with glycocalyx degradation and reduced microvascular perfusion. J Am Heart Assoc 8: e010647, 2019.
 307.West DC, Hampson IN, Arnold F, Kumar S. Angiogenesis induced by degradation products of hyaluronic acid. Science 228: 1324‐1326, 1985.
 308.Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNa guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the american college of cardiology/american heart association task force on clinical practice guidelines. Hypertension 71: 1269‐1324, 2017, 2018.
 309.White EJ, Gyulay G, Lhotak S, Szewczyk MM, Chong T, Fuller MT, Dadoo O, Fox‐Robichaud AE, Austin RC, Trigatti BL, Igdoura SA. Sialidase down‐regulation reduces non‐HDL cholesterol, inhibits leukocyte transmigration, and attenuates atherosclerosis in ApoE knockout mice. J Biol Chem 293: 14689‐14706, 2018.
 310.WHO. A revision of the system of nomenclature for influenza viruses: a WHO memorandum. Bull World Health Organ 58: 585‐591, 1980.
 311.Wiedermann CJ. Clinical review: Molecular mechanisms underlying the role of antithrombin in sepsis. Crit Care 10: 209, 2006.
 312.Wilson C, Lee MD, McCarron JG. Acetylcholine released by endothelial cells facilitates flow‐mediated dilatation. J Physiol 594: 7267‐7307, 2016.
 313.Wilson WW, Wade MM, Holman SC, Champlin FR. Status of methods for assessing bacterial cell surface charge properties based on zeta potential measurements. J Microbiol Methods 43: 153‐164, 2001.
 314.Wong M, Xu G, Barboza M, Maezawa I, Jin LW, Zivkovic A, Lebrilla CB. Metabolic flux analysis of the neural cell glycocalyx reveals differential utilization of monosaccharides. Glycobiology 30: 859‐871, 2020.
 315.Xu J, Mathur J, Vessieres E, Hammack S, Nonomura K, Favre J, Grimaud L, Petrus M, Francisco A, Li J, Lee V, Xiang FL, Mainquist JK, Cahalan SM, Orth AP, Walker JR, Ma S, Lukacs V, Bordone L, Bandell M, Laffitte B, Xu Y, Chien S, Henrion D, Patapoutian A. GPR68 senses flow and is essential for vascular physiology. Cell 173: 762.e716‐775.e716, 2018.
 316.Yalcin O, Jani VP, Johnson PC, Cabrales P. Implications enzymatic degradation of the endothelial glycocalyx on the microvascular hemodynamics and the arteriolar red cell free layer of the rat cremaster muscle. Front Physiol 9: 168, 2018.
 317.Yamaguchi K, Hata K, Koseki K, Shiozaki K, Akita H, Wada T, Moriya S, Miyagi T. Evidence for mitochondrial localization of a novel human sialidase (NEU4). Biochem J 390: 85‐93, 2005.
 318.Yamanami H, Shiozaki K, Wada T, Yamaguchi K, Uemura T, Kakugawa Y, Hujiya T, Miyagi T. Down‐regulation of sialidase NEU4 may contribute to invasive properties of human colon cancers. Cancer Sci 98: 299‐307, 2007.
 319.Yang B, Rizzo V. Shear stress activates eNOS at the endothelial apical surface through β1 containing integrins and caveolae. Cell Mol Bioeng 6: 346‐354, 2013.
 320.Yang H, Zhu L, Chao Y, Gu Y, Kong X, Chen M, Ye P, Luo J, Chen S. Hyaluronidase2 (Hyal2) modulates low shear stress‐induced glycocalyx impairment via the LKB1/AMPK/NADPH oxidase‐dependent pathway. J Cell Physiol 233: 9701‐9715, 2018.
 321.Yang J, LeBlanc ME, Cano I, Saez‐Torres KL, Saint‐Geniez M, Ng YS, D'Amore PA. ADAM10 and ADAM17 proteases mediate proinflammatory cytokine‐induced and constitutive cleavage of endomucin from the endothelial surface. J Biol Chem 295: 6641‐6651, 2020.
 322.Yang WH, Aziz PV, Heithoff DM, Mahan MJ, Smith JW, Marth JD. An intrinsic mechanism of secreted protein aging and turnover. Proc Natl Acad Sci U S A 112: 13657‐13662, 2015.
 323.Yang X, Meegan JE, Jannaway M, Coleman DC, Yuan SY. A disintegrin and metalloproteinase 15‐mediated glycocalyx shedding contributes to vascular leakage during inflammation. Cardiovasc Res 114: 1752‐1763, 2018.
 324.Zanini D, Göpfert MC. Mechanosensation: Tethered ion channels. Curr Biol 23: R349‐R351, 2013.
 325.Zeng Y. Endothelial glycocalyx as a critical signalling platform integrating the extracellular haemodynamic forces and chemical signalling. J Cell Mol Med 21: 1457‐1462, 2017.
 326.Zeng Y, Adamson RH, Curry F‐RE, Tarbell JM. Sphingosine‐1‐phosphate protects endothelial glycocalyx by inhibiting syndecan‐1 shedding. Am J Phys Heart Circ Phys 306: H363‐H372, 2014.
 327.Zeng Y, Liu X‐H, Tarbell J, Fu B. Sphingosine 1‐phosphate induced synthesis of glycocalyx on endothelial cells. Exp Cell Res 339: 90‐95, 2015.
 328.Zeng Y, Zhang XF, Fu BM, Tarbell JM. The role of endothelial surface glycocalyx in mechanosensing and transduction. Adv Exp Med Biol 1097: 1‐27, 2018.
 329.Zerda KS, Gerba CP, Hou KC, Goyal SM. Adsorption of viruses to charge‐modified silica. Appl Environ Microbiol 49: 91‐95, 1985.
 330.Zhang Z, Wuhrer M, Holst S. Serum sialylation changes in cancer. Glycoconj J 35: 139‐160, 2018.
 331.Zhou X, Yang G, Guan F. Biological functions and analytical strategies of sialic acids in tumor. Cells 9: 1‐18, 2020.
 332.Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117‐2128, 2015.
 333.Zou MH, Cohen R, Ullrich V. Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus. Endothelium 11: 89‐97, 2004.
 334.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) 99: 1471‐1476, 2005.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Christopher A. Foote, Rogerio N. Soares, Francisco I. Ramirez‐Perez, Thaysa Ghiarone, Annayya Aroor, Camila Manrique‐Acevedo, Jaume Padilla, Luis Martinez‐Lemus. Endothelial Glycocalyx. Compr Physiol 2022, 12: 1-31. doi: 10.1002/cphy.c210029