Hyaluronan regulates vascular smooth muscle cell osteogenic differentiation and vascular calcification

Roy, Shrea, Kane, Jamie, Grigorieva, Irina, Roche-Dugmore, Dylan, Moore, Sacha, Steadman, Robert ORCID: https://orcid.org/0000-0002-1303-2496, Raby, Anne-Catherine ORCID: https://orcid.org/0000-0002-5354-5835, Jakulj, Lily, Schurgers, Leon, Lutgens, Esther, Eringa, Etto C., Vervloet, Marc, Fraser, Donald ORCID: https://orcid.org/0000-0003-0102-9342 and Meran, Soma ORCID: https://orcid.org/0000-0003-3408-3978 2026. Hyaluronan regulates vascular smooth muscle cell osteogenic differentiation and vascular calcification. Biomolecules 16 (5) , 729. 10.3390/biom16050729

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Abstract

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-β1) 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Start Date: 2026-05-15
Publisher:	MDPI
Date of First Compliant Deposit:	3 June 2026
Date of Acceptance:	11 May 2026
Last Modified:	03 Jun 2026 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/187388

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