{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:54:23Z","timestamp":1792788863911,"version":"4.5.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Fabry disease (FD) is an X-linked multisystemic lysosomal storage disease due to a deficiency of \u03b1-galactosidase A (<jats:italic>GLA<\/jats:italic>\/AGAL). Progressive cellular accumulation of the AGAL substrate globotriaosylceramide (Gb<jats:sub>3<\/jats:sub>) leads to endothelial dysfunction. Here, we analyzed endothelial function <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> in an AGAL-deficient genetic background to identify the processes underlying this small vessel disease. Arterial stiffness and endothelial function was prospectively measured in five males carrying <jats:italic>GLA<\/jats:italic> variants (control) and 22 FD patients under therapy. AGAL-deficient endothelial cells (EA.hy926) and monocytes (THP1) were used to analyze endothelial glycocalyx structure, function, and underlying inflammatory signals. Glycocalyx thickness and small vessel function improved significantly over time (p&amp;lt;0.05) in patients treated with enzyme replacement therapy (ERT, n=16) and chaperones (n=6). AGAL-deficient endothelial cells showed reduced glycocalyx and increased monocyte adhesion (p&amp;lt;0.05). In addition, increased expression of angiopoietin-2, heparanase and NF-\u03baB was detected (all p&amp;lt;0.05). Incubation of wild-type endothelial cells with pathological globotriaosylsphingosine concentrations resulted in comparable findings. Treatment of AGAL-deficient cells with recombinant AGAL (p&amp;lt;0.01), heparin (p&amp;lt;0.01), anti-inflammatory (p&amp;lt;0.001) and antioxidant drugs (p&amp;lt;0.05), and a specific inhibitor (razuprotafib) of angiopoietin-1 receptor (Tie2) (p&amp;lt;0.05) improved glycocalyx structure and endothelial function <jats:italic>in vitro<\/jats:italic>. We conclude that chronic inflammation, including the release of heparanases, appears to be responsible for the degradation of the endothelial glycocalyx and may explain the endothelial dysfunction in FD. This process is partially reversible by FD-specific and anti-inflammatory treatment, such as targeted protective Tie2 treatment.<\/jats:p>","DOI":"10.3389\/fimmu.2021.789142","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T19:38:36Z","timestamp":1638387516000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation"],"prefix":"10.3389","volume":"12","author":[{"given":"Solvey","family":"Pollmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Scharnetzki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Manikowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Lenders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Brand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61589-5","article-title":"Fabry\u2019s Disease","volume":"372","author":"Zarate","year":"2004","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01486-1","article-title":"Fabry Disease: The Current Treatment Landscape","volume":"81","author":"Lenders","year":"2021","journal-title":"Drugs"},{"key":"B3","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.ymgme.2009.10.004","article-title":"Vasculopathy in Patients With Fabry Disease: Current Controversies and Research Directions","volume":"99","author":"Rombach","year":"2010","journal-title":"Mol Genet Metab"},{"key":"B4","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s00395-012-0311-3","article-title":"Pathologic Endothelial Response and Impaired Function of Circulating Angiogenic Cells in Patients With Fabry Disease","volume":"108","author":"Lorenzen","year":"2013","journal-title":"Basic Res Cardiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.79.3.581","article-title":"Identification of Distinct Luminal Domains for Macromolecules, Erythrocytes, and Leukocytes Within Mammalian Capillaries","volume":"79","author":"Vink","year":"1996","journal-title":"Circ Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0212-8","article-title":"The Endothelial Glycocalyx: Composition, Functions, and Visualization","volume":"454","author":"Reitsma","year":"2007","journal-title":"Pflugers Arch"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/anae.12661","article-title":"The Endothelial Glycocalyx: A Review of the Vascular Barrier","volume":"69","author":"Alphonsus","year":"2014","journal-title":"Anaesthesia"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.225268","article-title":"Imaging the Endothelial Glycocalyx In Vitro by Rapid Freezing\/Freeze Substitution Transmission Electron Microscopy","volume":"31","author":"Ebong","year":"2011","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s00418-015-1378-3","article-title":"Visualization of the Glomerular Endothelial Glycocalyx by Electron Microscopy Using Cationic Colloidal Thorium Dioxide","volume":"145","author":"Hegermann","year":"2016","journal-title":"Histochem Cell Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1080\/10739680590894966","article-title":"Microvascular Rheology and Hemodynamics","volume":"12","author":"Lipowsky","year":"2005","journal-title":"Microcirculation"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00592.2005","article-title":"Fluid Shear Stress Stimulates Incorporation of Hyaluronan Into Endothelial Cell Glycocalyx","volume":"290","author":"Gouverneur","year":"2006","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00051.2005","article-title":"Atherogenic Region and Diet Diminish Glycocalyx Dimension and Increase Intima-to-Media Ratios at Murine Carotid Artery Bifurcation","volume":"290","author":"van den Berg","year":"2006","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0590-6","article-title":"Impaired Glycocalyx Barrier Properties Contribute to Enhanced Intimal Low-Density Lipoprotein Accumulation at the Carotid Artery Bifurcation in Mice","volume":"457","author":"van den Berg","year":"2009","journal-title":"Pflugers Arch"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.118.310839","article-title":"Endothelial Glycocalyx as a Shield Against Diabetic Vascular Complications: Involvement of Hyaluronan and Hyaluronidases","volume":"38","author":"Dogn\u00e9","year":"2018","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/00126097-200008000-00007","article-title":"A Validation of the Mobil O Graph (Version 12) Ambulatory Blood Pressure Monitor","volume":"5","author":"Jones","year":"2000","journal-title":"Blood Press Monit"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/MBP.0b013e328339be38","article-title":"Evaluation of the Mobil-O-Graph New Generation ABPM Device Using the ESH Criteria","volume":"15","author":"Franssen","year":"2010","journal-title":"Blood Press Monit"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy339","article-title":"2018 ESC\/ESH Guidelines for the Management of Arterial Hypertension","volume":"39","author":"Williams","year":"2018","journal-title":"Eur Heart J"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e32832cb04e","article-title":"Noninvasive Determination of Carotid-Femoral Pulse Wave Velocity Depends Critically on Assessment of Travel Distance: A Comparison With Invasive Measurement","volume":"27","author":"Weber","year":"2009","journal-title":"J Hypertens"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e32834fa8b0","article-title":"Expert Consensus Document on the Measurement of Aortic Stiffness in Daily Practice Using Carotid-Femoral Pulse Wave Velocity","volume":"30","author":"Van Bortel","year":"2012","journal-title":"J Hypertens"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.176313","article-title":"Validation of a Brachial Cuff-Based Method for Estimating Central Systolic Blood Pressure","volume":"58","author":"Weber","year":"2011","journal-title":"Hypertension"},{"key":"B21","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ijcard.2013.08.079","article-title":"Noninvasive 24 H Ambulatory Monitoring of Aortic Wave Reflection and Arterial Stiffness by a Novel Oscillometric Device: The First Feasibility and Reproducibility Study","volume":"169","author":"Papaioannou","year":"2013","journal-title":"Int J Cardiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00751.2018","article-title":"Effects of High-Intensity Interval Training on Microvascular Glycocalyx and Associated microRNAs","volume":"316","author":"Schmitz","year":"2019","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s13054-016-1213-9","article-title":"A Guide to Human In Vivo Microcirculatory Flow Image Analysis","volume":"20","author":"Massey","year":"2016","journal-title":"Crit Care"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e96477","DOI":"10.1371\/journal.pone.0096477","article-title":"Deeper Penetration of Erythrocytes Into the Endothelial Glycocalyx Is Associated With Impaired Microvascular Perfusion","volume":"9","author":"Lee","year":"2014","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014121226","article-title":"Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease","volume":"27","author":"Lenders","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018070740","article-title":"Dose-Dependent Effect of Enzyme Replacement Therapy on Neutralizing Antidrug Antibody Titers and Clinical Outcome in Patients With Fabry Disease","volume":"29","author":"Lenders","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.06.007","article-title":"Effects of Orally Delivered Alpha-Galactosidase A on Gastrointestinal Symptoms in Patients With Fabry Disease","volume":"159","author":"Lenders","year":"2020","journal-title":"Gastroenterology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106005","article-title":"Mutation-Specific Fabry Disease Patient-Derived Cell Model to Evaluate the Amenability to Chaperone Therapy","volume":"56","author":"Lenders","year":"2019","journal-title":"J Med Genet"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 Years of Image Analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat Methods"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.5b00913","article-title":"Analysis of Total Human Urinary Glycosaminoglycan Disaccharides by Liquid Chromatography\u2013Tandem Mass Spectrometry","volume":"87","author":"Sun","year":"2015","journal-title":"Anal Chem"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00324-0","article-title":"HMG-CoA Reductase Inhibitors Decrease CD11b Expression and CD11b-Dependent Adhesion of Monocytes to Endothelium and Reduce Increased Adhesiveness of Monocytes Isolated From Patients With Hypercholesterolemia","volume":"30","author":"Weber","year":"1997","journal-title":"J Am Coll Cardiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI74527","article-title":"Targeting VE-PTP Activates TIE2 and Stabilizes the Ocular Vasculature","volume":"124","author":"Shen","year":"2014","journal-title":"J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150718","article-title":"Interfering With VE-PTP Stabilizes Endothelial Junctions In Vivo via Tie-2 in the Absence of VE-Cadherin","volume":"212","author":"Frye","year":"2015","journal-title":"J Exp Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv291","article-title":"Lyso-Gb3 Activates Notch1 in Human Podocytes","volume":"24","author":"Sanchez-Ni\u00f1o","year":"2015","journal-title":"Hum Mol Genet"},{"key":"B35","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13054-021-03520-w","article-title":"Identification of Novel Sublingual Parameters to Analyze and Diagnose Microvascular Dysfunction in Sepsis: The NOSTRADAMUS Study","volume":"25","author":"Rovas","year":"2021","journal-title":"Crit Care"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-020-09753-7","article-title":"Microvascular Dysfunction in COVID-19: The MYSTIC Study","volume":"24","author":"Rovas","year":"2021","journal-title":"Angiogenesis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvx023","article-title":"Endothelial Glycocalyx Breakdown is Mediated by Angiopoietin-2","volume":"113","author":"Lukasz","year":"2017","journal-title":"Cardiovasc Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1695768","article-title":"Tie2 Activation Promotes Protection and Reconstitution of the Endothelial Glycocalyx in Human Sepsis","volume":"119","author":"Drost","year":"2019","journal-title":"Thromb Haemost"},{"key":"B39","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s40942-020-00250-z","article-title":"The Tie2 Signaling Pathway in Retinal Vascular Diseases: A Novel Therapeutic Target in the Eye","volume":"6","author":"Nguyen","year":"2020","journal-title":"Int J Retina Vitreous"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.3390\/cells9081869","article-title":"Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab","volume":"9","author":"Khan","year":"2020","journal-title":"Cells"},{"key":"B41","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1167\/iovs.61.14.12","article-title":"A Small Molecule Inhibitor of VE-PTP Activates Tie2 in Schlemm's Canal Increasing Outflow Facility and Reducing Intraocular Pressure","volume":"61","author":"Li","year":"2020","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa213","article-title":"VE-PTP Inhibition Elicits eNOS Phosphorylation to Blunt Endothelial Dysfunction and Hypertension in Diabetes","volume":"117","author":"Siragusa","year":"2020","journal-title":"Cardiovasc Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s000180300001","article-title":"Molecular Mechanisms of N\u00acacetylcysteine Actions","volume":"60","author":"Zafarullah","year":"2003","journal-title":"Cell Molec Life Sci CMLS"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3727\/096368916X694265","article-title":"Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells","volume":"26","author":"Tseng","year":"2017","journal-title":"Cell Transplant"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.789142\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T19:38:38Z","timestamp":1638387518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.789142\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,30]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2021.789142"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.789142","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,30]]},"article-number":"789142"}}