{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:37:09Z","timestamp":1785418629770,"version":"3.56.0"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kidney Research UK, Kidney Wales","award":["ref ST_002_20220705"],"award-info":[{"award-number":["ref ST_002_20220705"]}]},{"award":["ref ST_002_20220705"],"award-info":[{"award-number":["ref ST_002_20220705"]}],"id":[{"id":"https:\/\/ror.org\/02kx7se86","id-type":"ROR","asserted-by":"publisher"}]},{"name":"European Union Horizon 2020 project IMPROVE-PD","award":["812699"],"award-info":[{"award-number":["812699"]}]},{"name":"Wellcome Trust-funded GW4-CAT HP Doctoral Fellowship","award":["341623\/Z\/25\/Z"],"award-info":[{"award-number":["341623\/Z\/25\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Vascular calcification is a strong predictor of cardiovascular mortality and lacks effective treatment. The transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes is a key driver of calcification. This study identifies a regulatory role for Hyaluronan (HA) in VSMC osteogenic differentiation and arterial calcification. Human aortic VSMCs stimulated with high phosphate and\/or pro-inflammatory cytokines (IL6 and TGF-\u03b21) exhibited increased RUNX2, alkaline phosphatase and osteopontin expression, along with reduced contractility and elevated calcium deposition. This corresponded with reduced HA deposition and downregulation of HA synthase enzymes (HAS1, HAS2), Hyaluronidase enzymes (Hyal1), and HA binding proteins (CD44, TSG-6), whilst HAS3 and versican were upregulated. Comparable alterations in HA and protein expression were observed in an in vivo model of arterial calcification using vitamin K-deficient warfarin-fed mice. Pharmacological inhibition of HA synthesis, enzyme-mediated HA degradation and siRNA\/plasmid modulation of HAS isoenzymes demonstrated a possible functional link between HA regulation and VSMC osteogenic differentiation. This study establishes HA and its associated binding proteins as key regulators of arterial calcification, highlighting a novel pathway for potential therapeutic intervention.<\/jats:p>","DOI":"10.3390\/biom16050729","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T10:07:47Z","timestamp":1779444467000},"page":"729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyaluronan Regulates Vascular Smooth Muscle Cell Osteogenic Differentiation and Vascular Calcification"],"prefix":"10.3390","volume":"16","author":[{"given":"Shrea","family":"Roy","sequence":"first","affiliation":[{"name":"Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0129-0075","authenticated-orcid":false,"given":"Jamie","family":"Kane","sequence":"additional","affiliation":[{"name":"Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Nephrology, Amsterdam University Medical Center, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Grigorieva","sequence":"additional","affiliation":[{"name":"Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9976-455X","authenticated-orcid":false,"given":"Dylan","family":"Roche-Dugmore","sequence":"additional","affiliation":[{"name":"Wales Kidney Research Unit, Division of Infection and 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University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Jakulj","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Amsterdam University Medical Center, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7867-6957","authenticated-orcid":false,"given":"Leon","family":"Schurgers","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Unversiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Lutgens","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine and Immunology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9814-5149","authenticated-orcid":false,"given":"Etto C.","family":"Eringa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Unversiteitssingel 50, 6229 ER Maastricht, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4607-9415","authenticated-orcid":false,"given":"Marc","family":"Vervloet","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Amsterdam University Medical Center, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Nephrology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-9342","authenticated-orcid":false,"given":"Donald","family":"Fraser","sequence":"additional","affiliation":[{"name":"Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soma","family":"Meran","sequence":"additional","affiliation":[{"name":"Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1056\/NEJMoa041031","article-title":"Chronic kidney disease and the risks of death, cardiovascular events, and 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