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

Viola Niemann¹Fedor Brack¹Luca Rolauer¹Janet Kaczur²Patrick Petzsch³Karl Köhrer³Christine Quast⁴Norbert Gerdes^4,5Pascal Bouvain⁶Katharina Voigt⁷Martina Krüger^5,7Alexander Brückner⁸Bernd K Fleischmann⁸Daniela Wenzel^8,9Philipp Barnowski^10,11,12,13Laura-Marie Zimmermann^11,12,13,14Sakine Simsekyilmaz¹⁵Timm Filler¹⁶Wiebke Ibing¹⁷Tobias Feige¹⁷Kim J Krott¹⁷Markus Udo Wagenhäuser¹⁷Jens W Fischer¹⁵Margitta Elvers¹⁷Gerhard Sengle^10,11,12,13Ulrich Flögel¹⁸Christian Hundhausen¹⁹Tatsiana Suvorava¹⁵Maria Grandoch^2,5*

• ¹Institute of Translational Pharmacology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
• ²Institute of Translational Pharmacology, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ³Biological and Medical Research Center (BMFZ), Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ⁴Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ⁵Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ⁶Institute of Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ⁷Institute for Cardiovascular Physiology, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ⁸Institute of Physiology I, Life and Brain Center, Medical Faculty and University of Bonn, Bonn, Germany
• ⁹Department of Systems Physiology, Medical Faculty, Ruhr University of Bochum, Bochum, Germany
• ¹⁰Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, Cologne, Germany
• ¹¹University of Cologne Center for Molecular Medicine Cologne, Cologne, Germany
• ¹²Universitat zu Koln Zentrum Biochemie, Cologne, Germany
• ¹³Cologne Center for Musculoskeletal Biomechanics (CCMB), Medical Faculty and University Hospital Cologne, Cologne, Germany
• ¹⁴Department of Pediatrics and Adolescent Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
• ¹⁵Institute of Pharmacology, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ¹⁶Department of Clinical Anatomy I, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ¹⁷Universitatsklinikum Dusseldorf Klinik fur Gefass- und Endovaskularchirurgie, Düsseldorf, Germany
• ¹⁸Institute for Molecular Cardiology, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
• ¹⁹Freelance Consultant, Düsseldorf, Germany

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. 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. 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. 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.