Hyaluronan synthase 3 deficiency lowers the incidence of ruptures of abdominal aortic aneurysms by reducing monocyte infiltration.

INTRODUCTION: Abdominal aortic aneurysms and dissections (AAA/AD) are vascular disorders with high mortality due to aortic ruptures. Critical pathomechanisms involve immune cell infiltration and degradation of the vascular extracellular matrix (ECM). Hyaluronan (HA), a major constituent of the ECM synthesized by three HA synthase isoenzymes (HAS1-3), plays a role in both processes. Specifically, HAS3 is crucially involved in inflammatory conditions. Here, we aimed to elucidate the role of HAS3-derived HA in AAA/AD.

METHODS: Mice double-deficient for and (-DKO) and littermate controls (-KO) were studied in a model of angiotensin II (AngII)-induced AAA/AD.

RESULTS: deficiency improved survival in -DKO mice reducing aortic ruptures. This was associated with decreased monocyte infiltration into the vessel wall. Aortic RNA-Seq analysis indicated disturbed immune cell adhesion and diapedesis. Transfer of deficient bone marrow into -DKO mice largely normalized the -DKO phenotype. While gene expression in endothelial cells (ECs) was not affected, AngII-induced upregulation of proinflammatory cytokines, adhesion receptors and the HA receptor CD44 was attenuated in DKO monocytes. This reduced CD44 cell surface expression in double-deficient monocytes, ultimately inhibiting their transmigration.

DISCUSSION: Our results show that HAS3 plays a key role in AAA/AD formation and suggest the HAS3/CD44 axis as promising therapeutic target to reduce monocyte recruitment and aortic rupture.

Copyright © 2025 Niemann, Brack, Rolauer, Kaczur, Petzsch, Köhrer, Quast, Gerdes, Bouvain, Voigt, Krüger, Brückner, Fleischmann, Wenzel, Barnowski, Zimmermann, Simsekyilmaz, Filler, Ibing, Feige, Krott, Wagenhäuser, Fischer, Elvers, Sengle, Flögel, Hundhausen, Suvorava and Grandoch.

PMID: 41280888