Hyaluronan synthase 3 deficiency lowers the incidence of ruptures of abdominal aortic aneurysms by reducing monocyte infiltration
Year: 2025
Type: article
Abstract: 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 apolipoprotein E and Has3 ( Apoe/Has3 -DKO) and littermate controls ( Apoe -KO) were studied in a model of angiotensin II (AngII)-induced AAA/AD. Results Has3 deficiency improved survival in Apoe/Has3 -DKO mice via 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 Apoe- deficient bone marrow into Apoe/Has3 -DKO mice largely normalized the Apoe/Has3 -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 Apoe/Has3- DKO monocytes. This reduced CD44 cell surface expression in Apoe/Has3- double-deficient monocytes, ultimately inhibiting their in vitro 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.
Source: Frontiers in Immunology
Authors: Viola Niemann, Fedor Brack, Luca Rolauer, Janet Kaczur, Patrick Petzsch, Karl Köhrer, Christine Quast, Norbert Gerdes, Pascal Bouvain, Katharina Voigt, Martina Krüger, Alexander Brückner, Bernd K. Fleischmann, Daniela Wenzel, Philipp Barnowski, Laura-Marie Zimmermann, Sakine Simsekyilmaz, Timm Filler, Wiebke Ibing, Tobias Feige, Kim J. Krott, Markus U. Wagenhäuser, Jens W. Fischer, Margitta Elvers, Gerhard Sengle, Ulrich Flögel, Christian Hundhausen, Tatsiana Suvorava, Maria Grandoch
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W4415960697