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

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 has been reported to be 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 AngiotensinII (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 abolished the Apoe/Has3-DKO phenotype . While endothelial cells were unaffected, AngII-induced upregulation of proinflammatory cytokines, adhesion receptors and the HA receptor CD44 was blunted in Apoe/Has3-DKO monocytes. Finally, lack of HAS3 reduced CD44 cell surface expression and subsequent monocyte transmigration.Our results show that HAS3/CD44-mediated monocyte recruitment plays a key role in AAA formation and may be a promising therapeutic target to reduce aortic rupture.