title: Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes.
abstract: Hyaluronic acid (HA) is a major component of the glycocalyx involved in the vascular wall and endothelial glomerular permeability barrier. Endocytosed hyaluronidase HYAL1 is known to degrade HA into small fragments in different cell types, including endothelial cells. In diabetes, the size and permeability of the glycocalyx are altered. In addition, patients with type 1 diabetes present increased plasma levels of both HA and HYAL1. To investigate the potential implication of HYAL1 in the development of diabetes-induced endothelium dysfunction, we measured endothelial markers, endothelium-dependent vasodilation, arteriolar glycocalyx size, and glomerular barrier properties in wild-type and HYAL1 knockout (KO) mice with or without streptozotocin (STZ)-induced diabetes. We observed that 4 weeks after STZ injections, the lack of HYAL1 1) prevents diabetes-induced increases in soluble P-selectin concentrations and limits the impact of the disease on endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation; 2) increases glycocalyx thickness and maintains glycocalyx structure and HA content during diabetes; and 3) prevents diabetes-induced glomerular barrier dysfunction assessed using the urinary albumin-to-creatinine ratio and urinary ratio of 70- to 40-kDa dextran. Our findings suggest that HYAL1 contributes to endothelial and glycocalyx dysfunction induced by diabetes. HYAL1 inhibitors could be explored as a new therapeutic approach to prevent vascular complications in diabetes.
authors.affiliation: Molecular Physiology Research Unit, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium sophie.dogne@unamur.be.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dogné
authors.affiliation: Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Rath
authors.affiliation: Groupe Interdisciplinaire de Génoprotéomique Appliquée, Cardiovascular Sciences, University of Liège, Liège, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Jouret
authors.affiliation: Molecular Physiology Research Unit, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Caron
authors.affiliation: Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.affiliation: Molecular Physiology Research Unit, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium.
authors.forename: Bruno
authors.identifier: 0000-0003-4458-7627
authors.initials: B
authors.lastname: Flamion
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D019276:Glycocalyx / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D006820:Hyaluronic Acid; C469220:Hyal1 protein, mouse; D006821:Hyaluronoglucosaminidase